pH sensitive prodrugs of 2,6-diisopropylphenol

ABSTRACT

The present invention is directed to water-soluble derivatives of 2,6-diisopropylphenol (Propofol). The compounds act as prodrugs of 2,6-diisopropylphenol and metabolize rapidly to Propofol thereby providing an alternative to the water-insoluble 2,6-diisopropylphenol. Pharmaceutical compositions comprising these compounds, methods of induction and maintenance of anesthesia or sedation as well as methods of treating neurodegenerative diseases utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.

CROSS REFERENCE TO RELATED APPLICATION(S)

This application is a continuation application of U.S. application Ser.No. 10/514,303 filed Nov. 11, 2004, now issued as U.S. Pat. No.7,250,412; which is a 35 USC § 371 National Stage application of PCTApplication No. PCT/US04/07935 filed Mar. 15, 2004; which claims thebenefit under 35 USC § 119(e) to U.S. Application Ser. No. 60/514,340filed Oct. 24, 2003, now abandoned. The disclosure of each of the priorapplications is considered part of and is incorporated by reference inthe disclosure of this application.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates generally to prodrugs and more specifically towater-soluble derivatives of 2,6-diisopropylphenol (Propofol).

2. Background Information

2,6-diisopropylphenol is highly lipophilic and is practically insolublein water. For intravenous applications, it is formulated in water usinga variety of solubilizing agents and/or emulsifiers. Examples of suchformulations include Cremophor™, Intralipid™, Diprivan™, Disoprofol™,Disoprivan™, and Rapinovet™. The aforementioned formulations have manylimitations. They cause allergic side effects and pain upon injection.Their preparation is difficult and costly and most importantly theycannot be sterilized and hence anti-microbial agents must be added tothe formulations.

Propofol or 2,6-diisopropylphenol is a short acting anesthetic that isadministered intravenously (i.v.) to mammalian subjects. The low watersolubility of this compound presents a significant formulationchallenge. The currently approved mode of administration for Propofol isan emulsion that has many disadvantages including costly preparation andsterilization procedures. Oxidation of Propofol to unwantedside-products in the presence of oxygen and light drastically shortensthe shelf life of such formulations. In addition, the oil-in-wateremulsions cause a number of clinical side effects including pain oninjection and pulmonary embolism.

Thus, there exists a clear need for a water-soluble, stable, non-toxicpharmaceutical composition of 2,6-diisopropylphenol.

SUMMARY OF THE INVENTION

The present invention describes non-toxic and water-soluble derivativesof 2,6-diisopropylphenol or Propofol, a low molecular weight alcoholthat is administered intravenously and serves as a sedative-hypnoticagent in humans and animals. 2,6-diisopropylphenol has a broad range ofapplications. It is an antioxidant and inhibits lipid peroxidation. Itcan also act as an anti-inflammatory agent and can useful in thetreatment of acid aspiration, respiratory distress syndrome, airwayobstructive disease, asthma, bronchiolitis, bronchopulmonary dysplasia,cancer, chronic obstructive pulmonary disease (“COPD”), cystic fibrosis,emphysema, HIV-associated lung disease, idiopathic pulmonary fibrosis,immune-complex-mediated lung injury, exposure to an oxidizing agent,ischemia-reperfusion injury, mineral dust pneumoconiosis, drug-inducedlung disease, silo-filler's disease, and various neurodegenerativediseases such as Friedrich's disease, Parkinson's disease, Alzheimer'sdisease, Huntington's disease, amyotrophic lateral sclerosis (ALS);multiple sclerosis (MS), Pick disease, spinal cord injury, acute neuralinjury and aging.

The present invention is directed to water-soluble derivatives of2,6-diisopropylphenol. The compounds of the invention act as pHsensitive prodrugs of 2,6-diisopropylphenol that degrade and metabolizerapidly to Propofol upon intravenous injection. The compounds of thisinvention are crystalline solids that are stable at or below ambienttemperature and can be stored as aqueous solutions if the pH of thesolution is kept in the range of 0 to 6. Such characteristics representclear economic and clinical improvements over the state of the art.

In one aspect, this invention describes 2,6-diisopropylphenolderivatives according to formula A:

-   -   wherein:    -   R₁ is hydrogen, alkyl, or aryl;    -   Each X is independently C₁₋₁₀ alkyl;    -   Y is heteroaryl, saturated heterocyclic, or NR₂R₃,    -   R₂ and R₃ are independently hydrogen, alkyl, or R₂ and R₃,        together with the nitrogen atom to which they are attached,        combine to form a saturated heterocyclic or heteroaryl ring;    -   or a pharmaceutically acceptable salt of any of the foregoing.

Specifically, the compounds of the present invention convert to2,6-diisopropylphenol in vivo and can be used as hypnotic agents,anti-convulsives, anti-pruritics, and anti-emetics. Other uses includetreatment of oxidative tissue damage, inflammation and cancer. Theprodrug compounds of the present invention have many advantages over2,6-diisopropylphenol by virtue of increased aqueous solubility andincreased stability towards oxidation over the parent compound thusmaking them particularly suitable for intravenous (i.v.) formulations.Therefore when used in a mammalian subject, the compounds of thisinvention replicate every therapeutic application that has beendescribed for 2,6-diisopropylphenol. Other advantages of the compoundsof the present invention include low toxicity and hightherapeutic-to-toxicity index.

In another aspect, this invention is directed to a pharmaceuticalcomposition comprising one or more compound (s) of Formula A, or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient.

In another aspect, this invention provides a method for inhibitingoxidation of biological material comprising contacting the material withan effective amount of a pharmaceutical composition comprising one ormore compound (s) of Formula A, or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable excipient.

In another aspect, this invention provides a method for the treatment ofa pathologic condition having an inflammatory component in a subjectcomprising administering to the subject a pharmaceutical compositioncomprising one or more compound (s) of Formula A, or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable excipient.

In another aspect, this invention provides a method for the treatment ofa pathologic condition of the nervous system having an inflammatorycomponent in a subject comprising administering to the subject apharmaceutical composition comprising one or more compound (s) ofFormula A, or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable excipient.

In another aspect, this invention provides a method for the treatment ofa pathologic respiratory condition in a subject comprising administeringto the subject a pharmaceutical composition comprising one or morecompound (s) of Formula A, or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable excipient.

In another aspect, this invention provides a method for inducinganesthesia in a subject comprising administering to the subject apharmaceutical composition comprising one or more compound (s) ofFormula A, or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable excipient.

In another aspect, this invention provides a method for inhibitingnausea and vomiting in a subject comprising administering to the subjecta pharmaceutical composition comprising one or more compound (s) ofFormula A, or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable excipient.

In another aspect, this invention provides a method for the treatment ofepileptic or convulsive disorders in a subject comprising administeringto the subject a pharmaceutical composition comprising one or morecompound (s) of Formula A, or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable excipient.

In another aspect, this invention provides a method for the treatment ofpruritis in a subject comprising administering to the subject apharmaceutical composition comprising one or more compound (s) ofFormula A, or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable excipient.

In another aspect, this invention provides pharmaceutical compositionscomprising at least one of the compounds of the invention, in apharmaceutically acceptable vehicle, for the treatment of carcinomas.Examples of carcinomas include mammary cancer, prostate cancer, kidneycancer, Karposi's sarcoma, colon cancer, cervical cancer, lung cancer,cutaneous T-cell lymphoma, cancer of the head and neck, cancers of theaerodigestive pathway, skin cancer, bladder cancer, sarcomas,leukoplakias, acute promyelocytic leukemia, and the like.

In another aspect, this invention provides pharmaceutical compositionscomprising at least one the compounds of the invention in combinationwith other chemotherapeutic agents, in a pharmaceutically acceptablevehicle, for the treatment of carcinomas. Examples of chemotherapeuticagents contemplated for use in the practice of this particular inventioninclude Busulfan, Carboplatin, Cisplatin, Cyclophosphamide, Cytosinearabinoside, Etoposide, 5-Fluorouracil, Melphalan, Methotrexate,Mitoxantrone, Taxol, Interferon, Fareston, Arzoxifene, Evista,Tamoxifen, and the like.

In another aspect, this invention provides a method for the treatment ofa subject undergoing treatment with a chemotherapeutic agent havingactivity as an oxidizing agent comprising the step of administering apharmaceutical composition comprising one or more compound (s) ofFormula A, or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable excipient.

In another aspect, this invention provides a method for the use ofcompounds of Formula A in the manufacture of a medicament for thetreatment of a pathological condition having an inflammatory component.

The non-limiting examples shown in schemes 1-3, illustrate theinventors' preferred methods for carrying out the preparative process ofthe invention.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect of the invention, there are provided compounds comprisingthe structural formula A:

-   -   wherein:    -   R₁ is hydrogen, alkyl, or aryl;    -   Each X is independently C₁₋₁₀ alkyl;    -   Y is heteroaryl, saturated heterocyclic, or NR₂R₃,    -   R₂ and R₃ are independently hydrogen, alkyl, or R₂ and R₃,        together with the nitrogen atom to which they are attached,        combine to form a saturated heterocyclic or heteroaryl ring; or        a pharmaceutically acceptable salt of any of the foregoing.

The compounds according to this invention may contain one or moreasymmetric carbon atoms and can thus occur as racemates and racemicmixtures, single enantiomers, diastereomeric mixtures or individualdiastereomers. The term “stereoisomer” refers to a chemical compoundhaving the same molecular weight, chemical composition, and constitutionas another, but with the atoms grouped differently. That is, certainidentical chemical moieties are at different orientations in space and,therefore, when pure, have the ability to rotate the plane of polarizedlight. However, some pure stereoisomers may have an optical rotationthat is so slight that it is undetectable with present instrumentation.The compounds described herein may have one or more asymmetrical carbonatoms and therefore include various stereoisomers. All such isomericforms of these compounds are expressly included in the presentinvention.

Each stereogenic carbon may be of R or S configuration. Although thespecific compounds exemplified in this application may be depicted in aparticular configuration, compounds having either the oppositestereochemistry at any given chiral center or mixtures thereof are alsoenvisioned. When chiral centers are found in the derivatives of thisinvention, it is to be understood that this invention encompasses allpossible stereoisomers.

The terms “optically pure compound” or “optically pure isomer” refers toa single stereoisomer of a chiral compound regardless of theconfiguration of the said compound.

For purpose of this application, all sugars are referenced usingconventional three-letter nomenclature. All sugars are assumed to be inthe D-form unless otherwise noted, except for fucose, which is in theL-form. Further, all sugars are in the pyranose form.

The compounds according to this invention may occur as a mixture oftautomers. The term “tautomer” or “tautomerism” refer to one of two ormore structural isomers that exist in equilibrium and are readilyconverted from one isomeric form to another. Examples of includeketo-enol tautomers, such as acetone/propen-2-ol and the like,ring-chain tautomers, such as glucose/2,3,4,5,6-pentahydroxy-hexanal andthe like. The compounds described herein may have one or more tautomersand therefore include various isomers. All such isomeric forms of thesecompounds are expressly included in the present invention. The followingexample of tautomerism is provided for reference:

The following example of nomenclature and numbering system is providedfor reference.

The term “substantially homogeneous” refers to collections of moleculeswherein at least 80%, preferably at least about 90% and more preferablyat least about 95% of the molecules are a single compound or a singlestereoisomer thereof.

As used herein, the term “attached” signifies a stable covalent bond,certain preferred points of attachment being apparent to those skilledin the art.

The terms “optional” or “optionally” refer to occurrence ornon-occurrence of the subsequently described event or circumstance, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not. In such context, the sentence“optionally substituted alkyl group” means that the alkyl group may ormay not be substituted and the description includes both a substitutedand an unsubstituted alkyl group.

The term “effective amount” of a compound refers a non-toxic butsufficient amount of the compound that provides a desired effect. Thisamount may vary from subject to subject, depending on the species, age,and physical condition of the subject, the severity of the disease thatis being treated, the particular compound used, its mode ofadministration, and the like. Therefore, it is difficult to generalizean exact “effective amount”, yet, a suitable effective amount may bedetermined by one of ordinary skill in the art.

The term “pharmaceutically acceptable” refers to a compound, additive orcomposition that is not biologically or otherwise undesirable. Forexample, the additive or composition may be administered to a subjectalong with a compound of the invention without causing any undesirablebiological effects or interacting in an undesirable manner with any ofthe other components of the pharmaceutical composition in which it iscontained.

The term “pharmaceutically acceptable salts” includes hydrochloric salt,hydrobromic salt, hydroiodic salt, hydrofluoric salt, sulfuric salt,citric salt, maleic salt, acetic salt, lactic salt, nicotinic salt,succinic salt, oxalic salt, phosphoric salt, malonic salt, salicylicsalt, phenylacetic salt, stearic salt, pyridine salt, ammonium salt,piperazine salt, diethylamine salt, nicotinamide salt, formic salt, ureasalt, sodium salt, potassium salt, calcium salt, magnesium salt, zincsalt, lithium salt, cinnamic salt, methylamino salt, methanesulfonicsalt, picric salt, tartaric salt, triethylamino salt, dimethylaminosalt, tris (hydroxymethyl)aminomethane salt and the like. Additionalpharmaceutically acceptable salts are known to those of skill in theart.

When used in conjunction with a compound of this invention, the terms“elicite”, “eliciting,” modulator”, “modulate”, “modulating”,“regulator”, “regulate” or “regulating” selective gene expression referto a compound that can act as an activator, an agonist, a pan-agonist oran antagonist of gene expression by a particular receptor, such as forexample a Retinoid X Receptor and the like.

The terms “therapeutic agent” and “chemotherapeutic agent”, refer to acompound or compounds and pharmaceutically acceptable compositionsthereof that are administered to mammalian subjects as prophylactic orremedy in the treatment of a disease or medical condition. Suchcompounds may be administered to the subject via oral formulation,transdermal formulation or by injection.

The term “Lewis acid” refers to a molecule that can accept an unsharedpair of electrons and as such would be obvious to one of ordinary skilland knowledge in the art. The definition of “Lewis acid” includes but isnot limited to: boron trifluoride, boron trifluoride etherate, borontrifluoride tetrahydrofuran complex, boron trifluoride tert-butyl-methylether complex, boron trifluoride dibutyl ether complex, borontrifluoride dihydrate, boron trifluoride di-acetic acid complex, borontrifluoride dimethyl sulfide complex, boron trichloride, borontrichloride dimethyl sulfide complex, boron tribromide, boron tribromidedimethyl sulfide complex, boron triiodide, triimethoxyborane,triethoxyborane, trimethylaluminum, triethylaluminum, aluminumtrichloride, aluminum trichloride tetrahydrofuran complex, aluminumtribromide, titanium tetrachloride, titanium tetrabromide, titaniumiodide, titanium tetraethoxide, titanium tetraisopropoxide, scandium(III) trifluoromethanesulfonate, yttrium (III)trifluoromethanesulfonate, ytterbium (III) trifluoromethanesulfonate,lanthanum (III) trifluoromethanesulfonate, zinc (II) chloride, zinc (II)bromide, zinc (II) iodide, zinc (II) trifluoromethanesulfonate, zinc(II) sulfate, magnesium sulfate, lithium perchlorate, copper (II)trifluoromethanesulfonate, copper (II) tetrafluoroborate and the like.Certain Lewis acids may have optically pure ligands attached to theelectron acceptor atom, as set forth in Corey, E. J. Angewandte Chemie,International Edition (2002), 41 (10), 1650-1667; Aspinall, H. C.Chemical Reviews (Washington, D.C., United States) (2002), 102 (6),1807-1850; Groger, H. Chemistry—A European Journal (2001), 7 (24),5246-5251; Davies, H. M. L. Chemtracts (2001), 14 (11), 642-645; Wan, Y.Chemtracts (2001), 14 (11), 610-615; Kim, Y. H. Accounts of ChemicalResearch (2001), 34 (12), 955-962; Seebach, D. Angewandte Chemie,International Edition (2001), 40 (1), 92-138; Blaser, H. U. AppliedCatalysis, A: General (2001), 221 (1-2), 119-143; Yet, L. AngewandteChemie, International Edition (2001), 40 (5), 875-877; Jorgensen, K. A.Angewandte Chemie, International Edition (2000), 39 (20), 3558-3588;Dias, L. C. Current Organic Chemistry (2000), 4 (3), 305-342; Spindler,F. Enantiomer (1999), 4 (6), 557-568; Fodor, K. Enantiomer (1999), 4(6), 497-511; Shimizu, K. D.; Comprehensive Asymmetric Catalysis 1-111(1999), 3, 1389-1399; Kagan, H. B. Comprehensive Asymmetric Catalysis1-111 (1999), 1, 9-30; Mikami, K. Lewis Acid Reagents (1999), 93-136 andall references cited therein. Such Lewis acids maybe used by one ofordinary skill and knowledge in the art to produce optically purecompounds from achiral starting materials.

The term “acylating agent” refers to a molecule that can transfer analkylcarbonyl, substituted alkylcarbonyl or aryl carbonyl group toanother molecule. The definition of “acylating agent” includes but isnot limited to ethyl acetate, vinyl acetate, vinyl propionate, vinylbutyrate, isopropenyl acetate, 1-ethoxyvinyl acetate, trichloroethylbutyrate, trifluoroethyl butyrate, trifluoroethyl laureate, S-ethylthiooctanoate, biacetyl monooxime acetate, acetic anhydride, acetylchloride, succinic anhydride, diketene, diallyl carbonate, carbonic acidbut-3-enyl ester cyanomethyl ester, amino acid and the like.

The term “nucleophile” or “nucleophilic reagent” refers to a negativelycharged or neutral molecule that has an unshared pair of electrons andas such would be obvious to one of ordinary skill and knowledge in theart. The definition of “nucleophile” includes but is not limited to:water, alkylhydroxy, alkoxy anion, arylhydroxy, aryloxy anion,alkylthiol, alkylthio anion, arylthiol, arylthio anion, ammonia,alkylamine, arylamine, alkylamine anion, arylamine anion, hydrazine,alkyl hydrazine, arylhydrazine, alkylcarbonyl hydrazine, arylcarbonylhydrazine, hydrazine anion, alkyl hydrazine anion, arylhydrazine anion,alkylcarbonyl hydrazine anion, arylcarbonyl hydrazine anion, cyanide,azide, hydride, alkyl anion, aryl anion and the like.

The term “electrophile” or “electrophilic reagent” refers to apositively charged or neutral molecule that has an open valence shelland as such would be obvious to one of ordinary skill and knowledge inthe art. The definition of “electrophile” includes but is not limitedto: hydronium, acylium, lewis acids, such as for example, borontrifluoride and the like, halogens, such as for example Br₂ and thelike, carbocations, such as for example tert-butyl cation and the like,diazomethane, trimethylsilyldiazomethane, alkyl halides, such as forexample methyl iodide, benzyl bromide and the like, alkyl triflates,such as for example methyl triflate and the like, alkyl sulfonates, suchas for example ethyl toluenesulfonate, butyl methanesulfonate and thelike, acyl halides, such as for example acetyl chloride, benzoyl bromideand the like, acid anhydrides, such as for example acetic anhydride,succinic anhydride, maleic anhydride and the like, isocyanates, such asfor example methyl isocyariate, phenylisocyanate and the like,chloroformates, such as for example methyl chloroformate, ethylchloroformate, benzyl chloroformate and the like, sulfonyl halides, suchas for example methanesulfonyl chloride, p-toluenesulfonyl chloride andthe like, silyl halides, such as for example trimethylsilyl chloride,tertbutyldimethyl silyll chloride and the like, phosphoryl halide suchas for example dimethyl chlorophosphate and the like,alpha-beta-unsaturated carbonyl compounds such as for example acrolein,methyl vinyl ketone, cinnamaldehyde and the like.

The term “leaving group” refers to any atom (or group of atoms) that isstable in its anion or neutral form after it has been displaced by anucleophile and as such would be obvious to one of ordinary skill andknowledge in the art. The definition of “leaving group” includes but isnot limited to: water, methanol, ethanol, chloride, bromide, iodide,methanesulfonate, tolylsulfonate, trifluoromethanesulfonate, acetate,trichloroacetate, benzoate and the like.

The term “oxidant” refers to any reagent that will increase theoxidation state of a carbon atom in the starting material by eitheradding an oxygen atom to this carbon or removing an electron from thiscarbon and as such would be obvious to one of ordinary skill andknowledge in the art. The definition of “oxidant” includes but is notlimited to: osmium tetroxide, ruthenium tetroxide, rutheniumtrichloride, potassium permanganate, meta-chloroperbenzoic acid,hydrogen peroxide, dimethyl dioxirane and the like.

The term “metal ligand” refers to a molecule that has an unshared pairof electrons and can coordinate to a metal atom and as such would beobvious to one of ordinary skill and knowledge in the art. Thedefinition of “metal ligand” includes but is not limited to: water,alkoxy anion, alkylthio anion, ammonia, trialkylamine, triarylamine,trialkylphosphine, triarylphosphine, cyanide, azide and the like.

The term “reducing reagent” refers to any reagent that will decrease theoxidation state of a carbon atom in the starting material by eitheradding a hydrogen atom to this carbon or adding an electron to thiscarbon and as such would be obvious to one of ordinary skill andknowledge in the art. The definition of “reducing reagent” includes butis not limited to: borane-dimethyl sulfide complex,9-borabicyclo[3.3.1.]nonane (9-BBN), catechol borane, lithiumborohydride, sodium borohydride, sodium borohydride-methanol complex,potassium borohydride, sodium hydroxyborohydride, lithiumtriethylborohydride, lithium n-butylborohydride, sodiumcyanoborohydride, calcium (II) borohydride, lithium aluminum hydride,diisobutylaluminum hydride, n-butyl-diisobutylaluminum hydride, sodiumbis-methoxyethoxyaluminum hydride, triethoxysilane,diethoxymethylsilane, lithium hydride, lithium, sodium, hydrogen Ni/B,and the like. Certain acidic and Lewis acidic reagents enhance theactivity of reducing reagents. Examples of such acidic reagents include:acetic acid, methanesulfonic acid, hydrochloric acid, and the like.Examples of such Lewis acidic reagents include: trimethoxyborane,triethoxyborane, aluminum trichloride, lithium chloride, vanadiumtrichloride, dicyclopentadienyl titanium dichloride, cesium fluoride,potassium fluoride, zinc (II) chloride, zinc (II) bromide, zinc (II)iodide, and the like.

The term “coupling reagent” refers to any reagent that will activate thecarbonyl of a carboxylic acid and facilitate the formation of an esteror amide bond. The definition of “coupling reagent” includes but is notlimited to: acetyl chloride, ethyl chloroformate,dicyclohexylcarbodiimide (DCC), diisopropyl carbodiiimide (DIC),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI),N-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu),4-nitrophenol, pentafluorophenol,2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU), O-benzotriazole-N,N,N′N′-tetramethyluronium hexafluorophosphate(HBTU), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP),benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate,bromo-trispyrrolidino-phosphonium hexafluorophosphate,2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TNTU), O—(N-succinimidyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TSTU), tetramethylfluoroformamidiniumhexafluorophosphate and the like.

The term “removable protecting group” or “protecting group” refers toany group which when bound to a functionality, such as the oxygen atomof a hydroxyl or carboxyl group or the nitrogen atom of an amino group,prevents reactions from occurring at these functional groups and whichprotecting group can be removed by conventional chemical or enzymaticsteps to reestablish the functional group. The particular removableprotecting group employed is not critical.

The definition of “hydroxyl protecting group” includes but is notlimited to:

a) Methyl, tert-butyl, allyl, propargyl, p-chlorophenyl,p-methoxyphenyl, p-nitrophenyl, 2,4-dinitrophenyl,2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl, methoxymethyl,methylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl,p-methoxy-benzyloxymethyl, p-nitrobenzyloxymethyl,o-nitrobenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl,tert-butoxymethyl, 4-pentenyloxymethyl, tert-butyldimethylsiloxymethyl,thexyldimethylsiloxymethyl, tert-butyldiphenylsiloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,menthoxymethyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl,1-[2-(trimethylsilyl)ethoxy]ethyl, 1-methyl-1-ethoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,1-methyl-1-phenoxyethyl, 2,2,2-trichloroethyl,1-dianisyl-2,2,2-trichloroethyl,1,1,1,3,3,3-hexafluoro-2-phenylisopropyl, 2-trimethylsilylethyl,2-(benzylthio)ethyl, 2-(phenylselenyl)ethyl, tetrahydropyranyl,3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl,4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl,4-methoxytetrahydropyranyl S,S-dioxide,1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl,tetrahydrofuranyl, tetrahydrothiofuranyl and the like;

b) Benzyl, 2-nitrobenzyl, 2-trifluoromethylbenzyl, 4-methoxybenzyl,4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl,4-phenylbenzyl, 4-acylaminobenzyl, 4-azidobenzyl,4-(methylsulfinyl)benzyl, 2,4-dimethoxybenzyl, 4-azido-3-chlorobenzyl,3,4-dimethoxybenzyl, 2,6-dichlorobenzyl, 2,6-difluorobenzyl,1-pyrenylmethyl, diphenylmethyl, 4,4′-dinitrobenzhydryl, 5-benzosuberyl,triphenylmethyl (Trityl), α-naphthyldiphenylmethyl,(4-Methoxyphenyl)-diphenyl-methyl, di-(p-methoxyphenyl)-phenylmethyl,tri-(p-methoxyphenyl)methyl,4-(4′-bromophenacyloxy)-phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′-dimethoxy-3″-[N-(imidazolylmethyl)]trityl,4,4′-dimethoxy-3″-[N-(imidazolylethyl)carbamoyl]trityl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl,4-(17-tetrabenzo[a,c,g,I]fluorenylmethyl)-4,4′-dimethoxytrityl,9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl and thelike;

c) Trimethylsilyl, triethylsilyl, triisopropylsilyl,dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl,tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,di-tert-butylmethylsilyl, tris(trimethylsilyl)silyl,(2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl,tert-butylmethoxyphenylsilyl, tert-butoxydiphenylsilyl and the like;

d) —C(O)R₂₀, where R₂₀ is selected from alkyl, substituted alkyl, aryland more specifically R₂₀=hydrogen, methyl, ethyl, tert-butyl,adamantyl, crotyl, chloromethyl, dichloromethyl, trichloromethyl,trifluoromethyl, methoxymethyl, triphenylmethoxymethyl, phenoxymethyl,4-chlorophenoxymethyl, phenylmethyl, diphenylmethyl, 4-methoxycrotyl,3-phenylpropyl, 4-pentenyl, 4-oxopentyl, 4,4-(ethylenedithio)pentyl,5-[3-bis(4-methoxyphenyl)hydroxymethylphenoxy]-4-oxopentyl, phenyl,4-methylphenyl, 4-nitrophenyl, 4-fluorophenyl, 4-chlorophenyl,4-methoxyphenyl, 4-phenylphenyl, 2,4,6-trimethylphenyl, α-naphthyl,benzoyl and the like;

e) —C(O)OR₂₀, where R₂₀ is selected from alkyl, substituted alkyl, aryland more specifically R₂₀=methyl, methoxymethyl, 9-fluorenylmethyl,ethyl, 2,2,2-trichloromethyl, 1,1-dimethyl-2,2,2-trichloroethyl,2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, isobutyl, tert-Butyl,vinyl, allyl, 4-nitrophenyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl,4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl,2-(methylthiomethoxy)ethyl, 2-dansenylethyl, 2-(4-nitrophenyl)ethyl,2-(2,4-dinitrophenyl)ethyl, 2-cyano-1-phenylethyl, thiobenzyl,4-ethoxy-1-naphthyl and the like.

The definition of “amino protecting group” includes but is not limitedto:

a) 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,[2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl,2-phosphonioethyl, 1-methyl-1-(triphenylphosphonio)ethyl,1,1-dimethyl-2-cyanoethyl, 2-dansylethyl, 2-(4-nitrophenyl)ethyl,4-phenylacetoxybenzyl, 4-azidobenzyl, 4-azidomethoxybenzyl,m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl,5-benzisoxazolylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl,m-nitrophenyl, 3,5-dimethoxybenzyl,1-methyl-1-(3,5-dimethoxyphenyl)ethyl, o-nitrobenzyl,α-methylnitropiperonyl, 3,4-dimethoxy-6-nitrobenzyl, N-benzenesulfenyl,N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl,N-pentachlorobenzenesulfenyl. N-2-nitro-4-methoxybenzenesulfenyl,N-triphenylmethylsulfenyl,N-1-(2,2,2-trifluoro-1,1-diphenyl)ethylsulfenyl,N-3-nitro-2-pyridinesulfenyl, N-p-toluenesulfonyl, N-benzenesulfonyl,N-2,3,6-trimethyl-4-methoxybenzenesulfonyl,N-2,4,6-trimethoxybenzene-sulfonyl,N-2,6-dimethyl-4-methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl,N-2,3,5,6-tetramethyl-4-methoxybenzenesulfonyl and the like;

b) —C(O)OR₂₀, where R₂₀ is selected from alkyl, substituted alkyl, aryland more specifically R₂₀=methyl, ethyl, 9-fluorenylmethyl,9-(2-sulfo)fluorenylmethyl. 9-(2,7-dibromo)fluorenylmethyl,17-tetrabenzo[a,c,g,i]fluorenylmethyl. 2-chloro-3-indenylmethyl,benz[f]inden-3-ylmethyl,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothloxanthyl)]methyl,1,1-dioxobenzo[b]thiophene-2-ylmethyl, 2,2,2-trichloroethyl,2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,2-chloroethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl,1-(3,5-di-tert-butylphenyl)-1-methylethyl, 2-(2′-pyridyl)ethyl,2-(4′-pyridyl)ethyl, 2,2-bis(4′-nitrophenyl)ethyl,N-(2-pivaloylamino)-1,1-dimethylethyl,2-[(2-nitrophenyl)dithio]-1-phenylethyl, tert-butyl, 1-adamantyl,2-adamantyl, Vinyl, allyl, 1-lsopropylallyl, cinnamyl. 4-nitrocinnamyl,3-(3^(/)-pyridyl)prop-2-enyl, 8-quinolyl, N-Hydroxypiperidinyl,alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl,p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl,9-anthrylmethyl, diphenylmethyl, tert-amyl, S-benzyl thiocarbamate,butynyl, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,2,2-dimethoxycarbonylvinyl, o-(N,N′-dimethylcarboxamido)benzyl,1,1-dimethyl-3-(N,N′-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl,di(2-pyridyl)methyl, 2-furanylmethyl, 2-Iodoethyl, isobornyl, isobutyl,isonicotinyl, p-(p′-methoxyphenylazo)benzyl, 1-methylcyclobutyl,1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,1-methyl-1-4′-pyridylethyl, phenyl, p-(phenylazo)benzyl,2,4,6-tri-methylphenyl, 4-(trimethylammonium)benzyl,2,4,6-trimethylbenzyl and the like.

The definition of “carboxyl protecting group” includes but is notlimited to:

2-N-(morpholino)ethyl, choline, methyl, methoxyethyl, 9-Fluorenylmethyl,methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl,methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl,pivaloyloxymethyl, phenylacetoxymethyl, triisopropylsilylmethyl,cyanomethyl, acetol, p-bromophenacyl, α-methylphenacyl,p-methoxyphenacyl, desyl, carboxamidomethyl,p-azobenzenecarboxamido-methyl, N-phthalimidomethyl,(methoxyethoxy)ethyl, 2,2,2-trichloroethyl, 2-fluoroethyl,2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 4-chlorobutyl, 5-chloropentyl,2-(trimethylsilyl)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl,2-(2-pyridyl)ethyl, 2-(p-methoxyphenyl)ethyl,2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl,2-(4-acetyl-2-nitrophenyl)ethyl, 2-cyanoethyl, heptyl, tert-butyl,3-methyl-3-pentyl, dicyclopropylmethyl, 2,4-dimethyl-3-pentyl,cyclopentyl, cyclohexyl, allyl, methallyl, 2-methylbut-3-en-2-yl,3-methylbut-2-(prenyl), 3-buten-1-yl, 4-(trimethylsilyl)-2-buten-1-yl,cinnamyl, α-methylcinnamyl, propargyl, phenyl, 2,6-dimethylphenyl,2,6-diisopropylphenyl, 2,6-di-tert-butyl-4-methylphenyl,2,6-di-tert-butyl-4-methoxyphenyl, p-(methylthio)phenyl,pentafluorophenyl, benzyl, triphenylmethyl, diphenylmethyl,bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl.5-dibenzosuberyl, 1-pyrenylmethyl,2-(trifluoromethyl)-6-chromonylmethyl, 2,4,6-trimethylbenzyl,p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl,2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-Sulfobenzyl,4-azidomethoxybenzyl,4-{a/-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino}benzyl,piperonyl, 4-picolyl, trimethylsilyl, triethylsilyl,tert-butyldimethylsilyl, isopropyldimethylsilyl, phenyldimethylsilyl,di-tert-butylmethylsilyl, triisopropylsilyl and the like.

The term “Amino acid” refers to any of the naturally occurring aminoacids, as well as synthetic analogs and derivatives thereof. Alpha-Aminoacids comprise a carbon atom to which is bonded an amino group, acarboxy group, a hydrogen atom, and a distinctive group referred to as a“side chain”. The side chains of naturally occurring amino acids arewell known in the art and include, for example, hydrogen (e.g., as inglycine), alkyl (e.g., as in alanine, valine, leucine, isoleucine,proline), substituted alkyl (e.g., as in threonine, serine, methionine,cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine,and lysine), arylalkyl (e.g., as in phenylalanine), substitutedarylalkyl (e.g., as in tyrosine), heteroarylalkyl (e.g., as intryptophan, histidine) and the like. One of skill in the art willappreciate that the term “amino acid” can also include beta-, gamma-,delta-, omega-amino acids, and the like. Unnatural amino acids are alsoknown in the art, as set forth in, Natchus, M. gram. Organic Synthesis:Theory and Applications (2001), 5, 89-196; Ager, D. J. Current Opinionin Drug Discovery & Development (2001), 4 (6), 800; Reginato, gram.Recent Research Developments in Organic Chemistry (2000), 4 (Pt. 1),351-359; Dougherty, D. A. Current Opinion in Chemical Biology (2000), 4(6), 645-652; Lesley, S. A. Drugs and the Pharmaceutical Sciences(2000), 101 (Peptide and Protein Drug Analysis), 191-205; Pojitkov, A.E. Journal of Molecular Catalysis B: Enzymatic (2000), 10 (1-3), 47-55;Ager, D. J. Speciality Chemicals (1999), 19 (1), 10-12, and allreferences cited therein. Stereoisomers (e.g., D-amino acids) of thetwenty conventional amino acids, unnatural amino acids such as alpha,alpha-disubstituted amino acids and other unconventional amino acids mayalso be suitable components for compounds of the present invention.Examples of unconventional amino acids include: 4-hydroxyproline,3-methylhistidine, 5-hydroxylysine, and other similar amino acids andimino acids (e.g., 4-hydroxyproline).

The term “N-protected amino acid” refers to any amino acid which has aprotecting group bound to the nitrogen of the amino functionality. Thisprotecting group prevents reactions from occurring at the aminofunctional group and can be removed by conventional chemical orenzymatic steps to reestablish the amino functional group. Theparticular protecting group employed is not critical.

The term “O-protected amino acid” refers to any amino acid which has aprotecting group bound to the oxygen of the carboxyl functionality. Thisprotecting group prevents reactions from occurring at the carboxylfunctional group and can be removed by conventional chemical orenzymatic steps to reestablish the carboxyl functional group. Theparticular protecting group employed is not critical.

The term “Prodrug” refers to an agent that is converted into the parentdrug in vivo. Prodrugs are often useful because, in some situations,they may be easier to administer than the parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. A prodrug may be converted into theparent drug by various mechanisms, including enzymatic processes andmetabolic hydrolysis. See Harper, “Drug Latentiation” in Jucker, ed.Progress in Drug Research 4:221-294 (1962); Morozowich et al.,“Application of Physical Organic Principles to Prodrug Design” in E. B.Roche ed. Design of Biopharmaceutical Properties through Prodrugs andAnalogs, APHA Acad. Pharm. Sci. (1977); Bioreversible Carriers in Drugin Drug Design, Theory and Application, E. B. Roche, ed., APHA Acad.Pharm. Sci. (1987); Design of Prodrugs, H. Bundgaard, Elsevier (1985);Wang et al. “Prodrug approaches to the improved delivery of peptidedrug” in Curr. Pharm. Design. 5 (4):265-287 (1999); Pauletti et al.(1997) Improvement in peptide bioavailability: Peptidomimetics andProdrug Strategies, Adv. Drug. Delivery Rev. 27:235-256; Mizen et al.(1998) “The Use of Esters as Prodrugs for Oral Delivery of .beta.-Lactamantibiotics,” Pharm. Biotech. 111,:345-365; Gaignault et al. (1996)“Designing Prodrugs and Bioprecursors I. Carrier Prodrugs,” Pract. Med.Chem. 671-696; Asgharnejad, “Improving Oral Drug Transport”, inTransport Processes in Pharmaceutical Systems, gram. L. Amidon, P. I.Lee and E. M. Topp, Eds., Marcell Dekker, p. 185-218 (2000); Balant etal., “Prodrugs for the improvement of drug absorption via differentroutes of administration”, Eur. J. Drug Metab. Pharmacokinet., 15 (2):143-53 (1990); Balimane and Sinko, “Involvement of multiple transportersin the oral absorption of nucleoside analogues”, Adv. Drug DeliveryRev., 39 (1-3): 183-209 (1999); Browne, “Fosphenytoin (Cerebyx)”, Clin.Neuropharmacol. 20 (1): 1-12 (1997); Bundgaard, “Bioreversiblederivatization of drugs—principle and applicability to improve thetherapeutic effects of drugs”, Arch. Pharm. Chemi 86 (1): 1-39 (1979);Bundgaard H. “Improved drug delivery by the prodrug approach”,Controlled Drug Delivery 17: 179-96 (1987); Bundgaard H. “Prodrugs as ameans to improve the delivery of peptide drugs”, Adv. Drug Delivery Rev.8 (1): 1-38 (1992); Fleisher et al. “Improved oral drug delivery:solubility limitations overcome by the use of prodrugs”, Adv. DrugDelivery Rev. 19 (2): 115-130 (1996); Fleisher et al. “Design ofprodrugs for improved gastrointestinal absorption by intestinal enzymetargeting”, Methods Enzymol. 112 (Drug Enzyme Targeting, Pt. A): 360-81,(1985); Farquhar D, et al., “Biologically ReversiblePhosphate-Protective Groups”, J. Pharm. Sci., 72 (3): 324-325 (1983);Freeman S, et al., “Bioreversible Protection for the Phospho Group:Chemical Stability and Bioactivation of Di (4-acetoxy-benzyl)Methylphosphonate with Carboxyesterase,” J. Chem. Soc., Chem. Commun.,875-877 (1991); Friis and Bundgaard, “Prodrugs of phosphates andphosphonates: Novel lipophilic alpha-acyloxyalkyl ester derivatives ofphosphate- or phosphonate containing drugs masking the negative chargesof these groups”, Eur. J. Pharm. Sci. 4: 49-59 (1996); Gangwar et al.,“Prodrug, molecular structure and percutaneous delivery”, Des. Biopharm.Prop. Prodrugs Analogs, [Symp.] Meeting Date 1976, 409-21. (1977);Nathwani and Wood, “Penicillins: a current review of their clinicalpharmacology and therapeutic use”, Drugs 45 (6): 866-94 (1993);Sinhababu and Thakker, “Prodrugs of anticancer agents”, Adv. DrugDelivery Rev. 19 (2): 241-273 (1996); Stella et al., “Prodrugs. Do theyhave advantages in clinical practice?”, Drugs 29 (5): 455-73 (1985); Tanet al. “Development and optimization of anti-HIV nucleoside analogs andprodrugs: A review of their cellular pharmacology, structure-activityrelationships and pharmacokinetics”, Adv. Drug Delivery Rev. 39 (1-3):117-151 (1999); Taylor, “Improved passive oral drug delivery viaprodrugs”, Adv. Drug Delivery Rev., 19 (2): 131-148 (1996); Valentinoand Borchardt, “Prodrug strategies to enhance the intestinal absorptionof peptides”, Drug Discovery Today 2 (4): 148-155 (1997); Wiebe andKnaus, “Concepts for the design of anti-HIV nucleoside prodrugs fortreating cephalic HIV infection”, Adv. Drug Delivery Rev.: 39(1-3):63-80 (1999); Waller et al., “Prodrugs”, Br. J. Clin. Pharmac. 28:497-507 (1989).

The terms “halogen”, “halide” or “halo” include fluorine, chlorine,bromine, and iodine.

The terms “alkyl” and “substituted alkyl” are interchangeable andinclude substituted and unsubstituted C₁-C₁₀ straight chain saturatedaliphatic hydrocarbon groups, substituted and unsubstituted C₂-C₁₀straight chain unsaturated aliphatic hydrocarbon groups, substituted andunsubstituted C₄-C₁₀ branched saturated aliphatic hydrocarbon groups,substituted and unsubstituted C₄-C₁₀ branched unsaturated aliphatichydrocarbon groups, substituted and unsubstituted C₃-C₈ cyclic saturatedaliphatic hydrocarbon groups, substituted and unsubstituted C₅-C₈ cyclicunsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms. For example, the definition of “alkyl” shall include butis not limited to: methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu),pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, ethenyl, propenyl,butenyl, penentyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl,undecenyl, isopropyl (i-Pr), isobutyl (1-Bu), tert-butyl (t-Bu),sec-butyl (s-Bu), isopentyl, neopentyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, methylcyclopropyl,ethylcyclohexenyl, butenylcyclopentyl, adamantyl, norbornyl and thelike. Alkyl substituents are independently selected from the groupcomprising halogen, —OH, —SH, —NH₂, —CN, —NO₂, ═O, ═CH₂, trihalomethyl,carbamoyl, arylC₀₋₁₀alkyl, heteroarylC₀₋₁₀alkyl, C₁₋₁₀alkyloxy,arylC₀₋₁₀alkyloxy, C₁₋₁₀alkylthio, arylC₀₋₁₀alkylthio, C₁₋₁₀alkylamino,arylC₀₋₁₀alkylamino, N-aryl-N—C₀₋₁₀alkylamino, C₁₋₁₀alkylcarbonyl,arylC₀₋₁₀alkylcarbonyl, C₁₋₁₀alkylcarboxy, arylC₀₋₁₀alkylcarboxy,C₁₋₁₀alkylcarbonylamino, arylC₀₋₁₀alkylcarbonylamino, tetrahydrofuryl,morpholinyl, piperazinyl, hydroxypyronyl, —C₀₋₁₀alkylCOOR₂₁ and—C₀₋₁₀alkylCONR₂₂R₂₃ wherein R₂₁, R₂₂ and R₂₃ are independently selectedfrom hydrogen, alkyl, aryl, or R₂₂ and R₂₃ are taken together with thenitrogen to which they are attached forming a saturated cyclic orunsaturated cyclic system containing 3 to 8 carbon atoms with at leastone substituent as defined herein.

The term “alkyloxy” (e.g. methoxy, ethoxy, propyloxy, allyloxy,cyclohexyloxy) represents a substituted or unsubstituted alkyl group asdefined above having the indicated number of carbon atoms attachedthrough an oxygen bridge. The term “alkyloxyalkyl” represents analkyloxy group attached through an alkyl or substituted alkyl group asdefined above having the indicated number of carbon atoms.

The term “alkylthio” (e.g. methylthio, ethylthio, propylthio,cyclohexenylthio and the like) represents a substituted or unsubstitutedalkyl group as defined above having the indicated number of carbon atomsattached through a sulfur bridge. The term “alkylthioalkyl” representsan alkylthio group attached through an alkyl or substituted alkyl groupas defined above having the indicated number of carbon atoms.

The term “alkylamino” (e.g. methylamino, diethylamino, butylamino,N-propyl-N-hexylamino, (2-cyclopentyl)propylamino, hexenylamino, and thelike) represents one or two substituted or unsubstituted alkyl groups asdefined above having the indicated number of carbon atoms attachedthrough an amine bridge. The substituted or unsubstituted alkyl groupsmaybe taken together with the nitrogen to which they are attachedforming a saturated cyclic or unsaturated cyclic system containing 3 to10 carbon atoms with at least one substituent as defined above. The term“alkylaminoalkyl” represents an alkylamino group attached through asubstituted or unsubstituted alkyl group as defined above having theindicated number of carbon atoms.

The term “alkylhydrazino” (e.g. methylhydrazino, diethylhydrazino,butylhydrazino, (2-cyclopentyl)propylhydrazino, cyclohexanehydrazino,and the like) represents one or two substituted or unsubstituted alkylgroups as defined above having the indicated number of carbon atomsattached through a nitrogen atom of a hydrazine bridge. The substitutedor unsubstituted alkyl groups maybe taken together with the nitrogen towhich they are attached forming a saturated cyclic or unsaturated cyclicsystem containing 3 to 10 carbon atoms with at least one substituent asdefined above. The term “alkylhydrazinoalkyl” represents analkylhydrazino group attached through a substituted or unsubstitutedalkyl group as defined above having the indicated number of carbonatoms.

The term “alkylcarbonyl” (e.g. cyclooctylcarbonyl, pentylcarbonyl,3-hexenylcarbonyl and the like) represents a substituted orunsubstituted alkyl group as defined above having the indicated numberof carbon atoms attached through a carbonyl group. The term“alkylcarbonylalkyl” represents an alkylcarbonyl group attached througha substituted or unsubstituted alkyl group as defined above having theindicated number of carbon atoms.

The term “alkylcarboxy” (e.g. heptylcarboxy, cyclopropylcarboxy,3-pentenylcarboxy and the like) represents an alkylcarbonyl group asdefined above wherein the carbonyl is in turn attached through anoxygen. The term “alkylcarboxyalkyl” represents an alkylcarboxy groupattached through an alkyl group as defined above having the indicatednumber of carbon atoms.

The term “alkylcarbonylamino” (e.g. hexylcarbonylamino,cyclopentylcarbonyl-aminomethyl, methylcarbonylaminophenyl and the like)represents an alkylcarbonyl group as defined above wherein the carbonylis in turn attached through the nitrogen atom of an amino group. Thenitrogen group may itself be substituted with a substituted orunsubstituted alkyl or aryl group. The term “alkylcarbonylaminoalkyl”represents an alkylcarbonylamino group attached through a substituted orunsubstituted alkyl group as defined above having the indicated numberof carbon atoms.

The term “alkylcarbonylhydrazino” (e.g. ethylcarbonylhydrazino,tert-butylcarbonylhydrazino and the like) represents an alkylcarbonylgroup as defined above wherein the carbonyl is in turn attached throughthe nitrogen atom of a hydrazino group.

The term “aryl” represents an unsubstituted, mono-, di- ortrisubstituted monocyclic, polycyclic, biaryl aromatic groups covalentlyattached at any ring position capable of forming a stable covalent bond,certain preferred points of attachment being apparent to those skilledin the art (e.g., 3-phenyl, 4-naphtyl and the like). The arylsubstituents are independently selected from the group comprisinghalogen, —OH, —SH, —CN, —NO₂, trihalomethyl, hydroxypyronyl, C₁₋₁₀alkyl,arylC₀₋₁₀alkyl, C₀₋₁₀alkyloxyC₀₋₁₀alkyl, arylC₀₋₁₀alkyloxyC₀₋₁₀alkyl,C₀₋₁₀alkylthioC₀₋₁₀alkyl, arylC₀₋₁₀alkylthioC₀₋₁₀alkyl,C₀₋₁₀alkylaminoC₀₋₁₀alkyl, arylC₀₋₁₀alkylaminoC₀₋₁₀alkyl,N-aryl-N—C₀₋₁₀alkylaminoC₀₋₁₀alkyl, C₁₋₁₀alkylcarbonylC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarbonylC₀₋₁₀alkyl, C₁₋₁₀alkylcarboxyC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarboxyC₀₋₁₀alkyl, C₀₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl, —C₀₋₁₀alkylCOOR₂₁, and—C₀₋₁₀alkylCONR₂₂R₂₃ wherein R₂₁, R₂₂ and R₂₃ are independently selectedfrom hydrogen, alkyl, aryl or R₂₂ and R₂₃ are taken together with thenitrogen to which they are attached forming a saturated cyclic orunsaturated cyclic system containing 3 to 8 carbon atoms with at leastone substituent as defined above.

The definition of “aryl” includes but is not limited to phenyl,biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl,indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl and thelike.

The term “arylalkyl” (e.g. (4-hydroxyphenyl)ethyl,(2-aminonaphthyl)hexenyl and the like) represents an aryl group asdefined above attached through a substituted or unsubstituted alkylgroup as defined above having the indicated number of carbon atoms.

The term “arylcarbonyl” (e.g. 2-thiophenylcarbonyl,3-methoxyanthrylcarbonyl and the like) represents an aryl group asdefined above attached through a carbonyl group.

The term “arylalkylcarbonyl” (e.g. (2,3-dimethoxyphenyl)propylcarbonyl,(2-chloronaphthyl)pentenyl-carbonyl and the like) represents anarylalkyl group as defined above wherein the alkyl group is in turnattached through a carbonyl.

The term “aryloxy” (e.g. phenoxy, naphthoxy, 3-methylphenoxy, and thelike) represents an aryl or substituted aryl group as defined abovehaving the indicated number of carbon atoms attached through an oxygenbridge. The term “aryloxyalkyl” represents an aryloxy group attachedthrough a substituted or unsubstituted alkyl group as defined abovehaving the indicated number of carbon atoms.

The term “arylthio” (e.g. phenylthio, naphthylthio, 3-bromophenylthio,and the like) represents an aryl or substituted aryl group as definedabove having the indicated number of carbon atoms attached through asulfur bridge. The term “arylthioalkyl” represents an arylthio groupattached through a substituted or unsubstituted alkyl group as definedabove having the indicated number of carbon atoms.

The term “arylamino” (e.g. phenylamino, diphenylamino, naphthylamino,N-phenyl-N-naphthylamino, o-methylphenylamino, p-methoxyphenylamino, andthe like) represents one or two aryl groups as defined above having theindicated number of carbon atoms attached through an amine bridge. Theterm “arylaminoalkyl” represents an arylamino group attached through asubstituted or unsubstituted alkyl group as defined above having theindicated number of carbon atoms. The term “arylalkylamino” representsan aryl group attached through an alkylamino group as defined abovehaving the indicated number of carbon atoms. The term“N-aryl-N-alkylamino” (e.g. N-phenyl-N-methylamino,N-naphthyl-N-butylamino, and the like) represents one aryl and one asubstituted or unsubstituted alkyl group as defined above having theindicated number of carbon atoms independently attached through an aminebridge.

The term “arylhydrazino” (e.g. phenylhydrazino, naphthylhydrazino,4-methoxyphenylhydrazino, and the like) represents one or two arylgroups as defined above having the indicated number of carbon atomsattached through a hydrazine bridge. The term “arylhydrazinoalkyl”represents an arylhydrazino group attached through a substituted orunsubstituted alkyl group as defined above having the indicated numberof carbon atoms. The term “arylalkylhydrazino” represents an aryl groupattached through an alkylhydrazino group as defined above having theindicated number of carbon atoms. The term “N-aryl-N-alkylhydrazino”(e.g. N-phenyl-N-methylhydrazino, N-naphthyl-N-butylhydrazino, and thelike) represents one aryl and one a substituted or unsubstituted alkylgroup as defined above having the indicated number of carbon atomsindependently attached through an amine atom of a hydrazine bridge.

The term “arylcarboxy” (e.g. phenylcarboxy, naphthylcarboxy,3-fluorophenylcarboxy and the like) represents an arylcarbonyl group asdefined above wherein the carbonyl is in turn attached through an oxygenbridge. The term “arylcarboxyalkyl” represents an arylcarboxy groupattached through a substituted or unsubstituted alkyl group as definedabove having the indicated number of carbon atoms.

The term “arylcarbonylamino” (e.g. phenylcarbonylamino,naphthylcarbonylamino, 2-methylphenylcarbonylamino and the like)represents an arylcarbonyl group as defined above wherein the carbonylis in turn attached through the nitrogen atom of an amino group. Thenitrogen group may itself be substituted with an a substituted orunsubstituted alkyl or aryl group. The term “arylcarbonylaminoalkyl”represents an arylcarbonylamino group attached through a substituted orunsubstituted alkyl group as defined above having the indicated numberof carbon atoms. The nitrogen group may itself be substituted with asubstituted or unsubstituted alkyl or aryl group.

The term “arylcarbonylhydrazino” (e.g. phenylcarbonylhydrazino,naphthylcarbonylhydrazino, and the like) represents an arylcarbonylgroup as defined above wherein the carbonyl is in turn attached throughthe nitrogen atom of a hydrazino group.

The terms “heteroaryl”, “heterocycle” or “heterocyclic” refers to amonovalent unsaturated group having a single ring or multiple condensedrings, from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selectedfrom nitrogen, sulfur or oxygen within the ring. The heteroaryl groupsin this invention can be optionally substituted with 1 to 3 substituentsselected from the group comprising: halogen, —OH, —SH, —CN, —NO₂,trihalomethyl, hydroxypyronyl, C₁₋₁₀alkyl, arylC₀₋₁₀alkyl,C₀₋₁₀alkyloxyC₀₋₁₀alkyl, arylC₀₋₁₀alkyloxyC₀₋₁₀alkyl,C₀₋₁₀alkylthioC₀₋₁₀alkyl, arylC₀₋₁₀alkylthioC₀₋₁₀alkyl,C₀₋₁₀alkylaminoC₀₋₁₀alkyl, arylC₀₋₁₀alkylaminoC₀₋₁₀alkyl,N-aryl-N—C₀₋₁₀alkylaminoC₀₋₁₀alkyl, C₁₋₁₀alkylcarbonylC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarbonylC₀₋₁₀alkyl, C₁₋₁₀alkylcarboxyC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarboxyC₀₋₁₀alkyl, C₁₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl, —C₀₋₁₀alkylCOOR₂₁, and—C₀₋₁₀alkylCONR₂₂R₂₃ wherein R₂₁, R₂₂ and R₂₃ are independently selectedfrom hydrogen, alkyl, aryl, or R₂₂ and R₂₃ are taken together with thenitrogen to which they are attached forming a saturated cyclic orunsaturated cyclic system containing 3 to 8 carbon atoms with at leastone substituent as defined above.

The definition of “heteroaryl” includes but is not limited to thienyl,benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl,benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl,pyrrolyl-2,5-dione, 3-pyrrolinyl, indolyl, isoindolyl, 3H-indolyl,indolinyl, indolizinyl, indazolyl, phthalimidyl (orisoindoly-1,3-dione), imidazolyl, 2H-imidazolinyl, benzimidazolyl,pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl,isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl,piperonyl, purinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl,isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl,oxadiazolyl, thiadiazolyl, pyrrolidinyl-2,5-dione,imidazolidinyl-2,4-dione, 2-thioxo-imidazolidinyl-4-one,imidazolidinyl-2,4-dithione, thiazolidinyl-2,4-dione,4-thioxo-thiazolidinyl-2-one, piperazinyl-2,5-dione,tetrahydro-pyridazinyl-3,6-dione,1,2-dihydro-[1,2,4,5]tetrazinyl-3,6-dione,[1,2,4,5]tetrazinanyl-3,6-dione, dihydro-pyrimidinyl-2,4-dione,pyrimidinyl-2,4,6-trione and the like. For the purposes of thisapplication, the terms “heteroaryl”, “heterocycle” or “heterocyclic” donot include carbohydrate rings (i.e. mono- or oligosaccharides).

The term “saturated heterocyclic” represents an unsubstituted, mono-,di- or trisubstituted monocyclic, polycyclic saturated heterocyclicgroup covalently attached at any ring position capable of forming astable covalent bond, certain preferred points of attachment beingapparent to those skilled in the art (e.g., 1-piperidinyl, 4-piperazinyland the like).

The saturated heterocyclic substituents are independently selected fromthe group comprising halo, —OH, —SH, —CN, —NO₂, trihalomethyl,hydroxypyronyl, C₁₋₁₀alkyl, arylC₀₋₁₀alkyl, C₀₋₁₀alkyloxyC₀₋₁₀alkyl,arylC₀₋₁₀alkyloxyC₀₋₁₀alkyl, C₀₋₁₀alkylthioC₀₋₁₀alkyl,arylC₀₋₁₀alkylthioC₀₋₁₀alkyl, C₀₋₁₀alkylaminoC₀₋₁₀alkyl,arylC₀₋₁₀alkylaminoC₀₋₁₀alkyl, N-aryl-N—C₀₋₁₀alkylaminoC₀₋₁₀alkyl,C₁₋₁₀alkylcarbonylC₀₋₁₀alkyl, arylC₀₋₁₀alkylcarbonylC₀₋₁₀alkyl,C₁₋₁₀alkylcarboxyC₀₋₁₀alkyl, arylC₀₋₁₀alkylcarboxyC₀₋₁₀alkyl,C₁₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl,arylC₀₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl, —C₀₋₁₀alkylCOOR₂₁, and—C₀₋₁₀alkylCONR₂₂R₂₃ wherein R₂₁, R₂₂ and R₂₃ are independently selectedfrom hydrogen, alkyl, aryl, or R₂₂ and R₂₃ are taken together with thenitrogen to which they are attached forming a saturated cyclic orunsaturated cyclic system containing 3 to 8 carbon atoms with at leastone substituent as defined above.

The definition of saturated heterocyclic includes but is not limited topyrrolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl,1,4-dithienyl, thiomorpholinyl, piperazinyl, quinuclidinyl, and thelike.

The term “alpha-beta-unsaturated carbonyl” refers to a molecule that hasa carbonyl group directly attached to a double or triple bonded cabonand which would be obvious to one of ordinary skill and knowledge in theart. The definition of alpha-beta-unsaturated carbonyl includes but isnot limited to acrolein, methyl vinyl ketone, and the like.

The term “method” refers to manners, means, techniques and proceduresfor accomplishing a given task including, but not limited to, thosemanners, means, techniques and procedures either known to, or readilydeveloped from known manners, means, techniques and procedures by,practitioners of the chemical, pharmaceutical, biological, biochemicaland medical arts.

As used herein, the term “modulation” or “modulating” refers to thealteration of the catalytic activity of an enzyme or receptor in vitroand/or in vivo.

“In vitro” refers to procedures performed in an artificial environmentsuch as, such as for example, without limitation, in a test tube orculture medium. The skilled artisan will understand that, for example,an isolated enzyme and/or receptor may be contacted with a modulator inan in vitro environment. Alternatively, an isolated cell may becontacted with a modulator in an in vitro environment.

As used herein, “in vivo” refers to procedures performed within a livingorganism such as, without limitation, a mouse, rat, rabbit, ungulate,bovine, equine, porcine, canine, feline, primate, or human.

The term “organism” refers to any living entity comprised of at leastone cell. A living organism can be as simple as, for example, a singleeukaryotic cell or as complex as a mammal, including a human being.

The term “therapeutically effective amount” as used herein refers tothat amount of the compound being administered which will relieve tosome extent one or more of the symptoms of the disorder being treated.For example, in reference to the treatment of cancer, a therapeuticallyeffective amount refers to that amount which has the effect of (1)reducing the size of the tumor, (2) inhibiting (that is, slowing to someextent, preferably stopping) tumor metastasis, (3) inhibiting to someextent (that is, slowing to some extent, preferably stopping) tumorgrowth, and/or, (4) relieving to some extent (or, preferably,eliminating) one or more symptoms associated with the cancer.

“Pharmaceutically acceptable salt” refers to those salts which retainthe biological effectiveness and properties of the free bases and whichare obtained by reaction with inorganic or organic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, malic acid, maleic acid,succinic acid, tartaric acid, citric acid, and the like.

A “pharmaceutical composition” refers to a mixture of one or more of thecompounds described herein, or a pharmaceutically acceptable saltsthereof, with other chemical components, such as physiologicallyacceptable carriers and excipients. The purpose of a pharmaceuticalcomposition is to facilitate administration of a compound to anorganism.

As used herein, a “pharmaceutically acceptable carrier” refers to acarrier or diluent that does not cause significant irritation to anorganism and does not abrogate the biological activity and properties ofthe administered compound.

An “excipient” refers to an inert substance added to a pharmaceuticalcomposition to further facilitate administration of a compound.Examples, without limitation, of excipients include calcium carbonate,calcium phosphate, various sugars and types of starch, cellulosederivatives, gelatin, vegetable oils and polyethylene glycols.

“Treating” or “treatment” of a disease includes preventing the diseasefrom occurring in an animal that may be predisposed to the disease butdoes not yet experience or exhibit symptoms of the disease (prophylactictreatment), inhibiting the disease (slowing or arresting itsdevelopment), providing relief from the symptoms or side-effects of thedisease (including palliative treatment), and relieving the disease(causing regression of the disease).

A “subject” of treatment is an animal, such as a mammal, including ahuman. Animals subject to treatment include, for example, fish, birds,and mammals such as cows, sheep, pigs, horses, dogs, cats and the like.

A “therapeutic treatment” is a treatment administered to a subject whoexhibits signs of pathology for the purpose of diminishing oreliminating those signs.

Preferred compounds of the present invention also includepharmaceutically acceptable salts of the compounds of the aboveformulae. A “pharmaceutically acceptable salt” is a salt that can beformulated into a compound for pharmaceutical use including, such as forexample, metal salts (sodium, potassium, magnesium, calcium, etc.) andsalts of ammonia or organic amines.

In one aspect, the invention relates to pharmaceutical compositionscomprising at least one of the compounds of the invention, as well aspharmaceutically acceptable prodrugs and salts of such compounds, in apharmaceutically acceptable vehicle, for enteral, parenteral, topical orocular administration.

In another aspect, the invention relates to pharmaceutical compositionscomprising at least one of the compounds of the invention, as well aspharmaceutically acceptable prodrugs and salts of such compounds, in apharmaceutically acceptable vehicle, for the prophylactic andtherapeutic treatment of subjects as described herein.

In another aspect, the invention relates to pharmaceutical compositionscomprising at least one of the compounds of the invention, as well aspharmaceutically acceptable prodrugs and salts of such compounds, in apharmaceutically acceptable vehicle, for inhibiting oxidation inbiological materials. The methods involve contacting the biologicalmaterial with an effective amount of the compound. In the therapeuticmethods of this invention, a pharmacologically effective amount of thecompound is administered to a subject suffering from a pathologicalcondition responsive to inhibition of oxidation. In the prophylacticmethods of this invention a pharmaceutically effective amount of thecompound is administered to a subject at risk of developing a disease asa result of exposure to oxidative stress.

In another aspect, the invention relates to pharmaceutical compositionscomprising at least one of the compounds of the invention, as well aspharmaceutically acceptable prodrugs and salts of such compounds, in apharmaceutically acceptable vehicle, for the treatment or prevention ofconditions having an inflammatory component. A pharmacologicallyeffective amount of the compound is administered to a subject sufferingfrom, or at risk of suffering from, a pathological condition that can beimproved by inhibiting inflammation. In general, an effective dose isabout 100 milligram to about 1 gram taken orally per day.

In another aspect, the invention relates to pharmaceutical compositionscomprising at least one of the compounds of the invention, as well aspharmaceutically acceptable prodrugs and salts of such compounds, in apharmaceutically acceptable vehicle, for treating arthritis, bothrheumatoid arthritis and osteoarthritis. The compounds preferably aredelivered orally or transdermally for this purpose. A pharmacologicallyeffective amount of the agent taken orally is about 50 milligram toabout 2 gram daily.

In yet another aspect, the invention relates to pharmaceuticalcompositions comprising at least one of the compounds of the invention,as well as pharmaceutically acceptable prodrugs and salts of suchcompounds, in a pharmaceutically acceptable vehicle, for theprophylactic or therapeutic treatment of respiratory disorders thatinvolve an inflammatory component. Examples of respiratory diseases thatcan be treated with these compounds include acid aspiration,adult/infant respiratory distress syndrome, airway obstructive disease,asthma, bronchiolitis, bronchopulmonary dysplasia, cancer, chronicobstructive pulmonary disease (“COPD”), cystic fibrosis, emphysema,HIV-associated lung disease, idiopathic pulmonary fibrosis,immune-complex-mediated lung injury, exposure to an oxidizing agent,ischemia-reperfusion injury, mineral dust pneumoconiosis, drug-inducedlung disease, silo-filler's disease and the like. In the treatment ofrespiratory conditions, the compound is preferably delivered byinhalation. The compound can be delivered as an aerosol, mist or powder.An effective amount for delivery by inhalation is about 0.1 milligram to10 milligram per inhalation, several times daily. The compound also canbe delivered orally in amounts of about 50 milligram to about 2 gramdaily.

In another aspect, the invention relates to pharmaceutical compositionscomprising at least one of the compounds of the invention, as well aspharmaceutically acceptable prodrugs and salts of such compounds, in apharmaceutically acceptable vehicle, for the treatment of nervous systemdisorders. Examples of such neurodegenerative conditions of the nervoussystem include Friedrich's disease, Parkinson's disease, Alzheimer'sdisease, Huntington's disease, Pick disease, amyotrophic lateralsclerosis, multiple sclerosis and the like.

In another aspect, the invention relates to pharmaceutical compositionscomprising at least one of the compounds of the invention, as well aspharmaceutically acceptable prodrugs and salts of such compounds, in apharmaceutically acceptable vehicle, for treating trauma to the centralnervous system. Examples of such trauma include skull fracture and itsresulting edema, concussion, contusion, brain hemorrhages, shearinglesions, subdural hematoma, epidural hematoma, spinal cord injury andthe like. In the treatment of traumatic conditions of the centralnervous system, the compound preferably is administered parenterally,such as by intravenous injection or injection directly into the centralnervous system (i.e., intrathecally (IT) or into the brain). Apharmacologically effective amount of the compound is about 25 milligramto about 500 milligram i.v. or i.m. and about 5 milligram to about 100milligram IT. The treatment of chronic neurodegenerative disease is besteffected via oral administration of an effective amount of the compound,preferably 50 milligram to 2 gram daily.

In another aspect, the invention relates to pharmaceutical compositionscomprising at least one of the compounds of the invention, as well aspharmaceutically acceptable prodrugs and salts of such compounds, in apharmaceutically acceptable vehicle, for preventing/treatingcardiovascular disease, including but not limited toischemia-reperfusion dysfunction, atherosclerosis and restenosisfollowing angioplasty. Oral, enteral or intravenous administration isuseful for this purpose.

In another aspect, the invention relates to pharmaceutical compositionscomprising at least one of the compounds of the invention, as well aspharmaceutically acceptable prodrugs and salts of such compounds, in apharmaceutically acceptable vehicle, for the treatment of cancer or asadjuvants in the treatment of cancer. Co-administered withchemotherapeutic agents, they enhance cytotoxicity, thereby inhibitingthe growth of tumors. In addition, they also inhibit oxidative damagethat generally accompanies use of anticancer agents. Methods of treatingcancer involve administering a pharmacologically effective amount of thecompound to a subject prior to, during or after chemotherapy. Thecompounds are useful in the treatment of any cancer. However, they areparticularly effective in the treatment of colorectal cancer and lungcancer. The compounds also are effective with chemotherapeutic agentsthat act by all known modes of action. In such treatments, the compoundspreferably are delivered as a pharmaceutical composition in the form ofan intravenous or intramuscular solution. However, other modes ofdelivery, such as enteral administration, also are useful. An effectiveamount of the agent is about 50 milligram to about 2 gram delivereddaily over the course of the chemotherapy regimen.

In yet another aspect, the invention relates to pharmaceuticalcompositions containing the novel compounds of the invention incombination with other therapeutic agents and to methods of treatingdiseases and/or conditions using the same. Example of diseases and/orconditions include cancer, mammary cancer, prostate cancer, kidneycancer, Karposi's sarcoma, colon cancer, cervical cancer, lung cancer,cutaneous T-cell lymphoma, cancer of the head and neck, cancers of theaerodigestive pathway, skin cancer, bladder cancer, sarcomas,leukoplakias, acute promyelocytic leukemia and the like. Examples ofother therapeutic agents include Busulfan, Carboplatin, Cisplatin,Cyclophosphamide, Cytosine arabinoside, Etoposide, 5-Fluorouracil,Melphalan, Methotrexate, Mitoxantrone, Taxol, Interferon, Fareston,Arzoxifene, Evista, Tamoxifen, and the like.

In another aspect, the invention relates to the use of pharmaceuticalcompositions comprising at least one of the compounds of the invention,as well as pharmaceutically acceptable prodrugs and salts of suchcompounds, in a pharmaceutically acceptable vehicle, as hypnotic agentsfor the same indications as 2,6-diisopropylphenol. Examples of suchindications include inducing and/or maintaining general anaesthesia, useas a sedative and the like. The compound is administered in an amounteffective to induce hypnosis. For use as a general anaesthetic, thecompounds are preferably administered as an intravenous aqueoussolution. However, they also can be administered by inhalation. For useas a sedative (such as for example, for the treatment of anxietyconditions), the compounds are preferably and effectively administeredorally in amounts of about 10 milligram to 2 gram daily. However, theycan also be administered by inhalation, intravenously orintramuscularly.

The novel compounds of this invention can be administered in similaramounts and in the same schedule as injectable emulsions of DIPRIVAN™.Dosage level of 2,6-diisopropylphenol for producing general anesthesia,both induction (for example about 2.0 to about 2.5 milligram/kg for anadult) and maintenance (for example, about 4 to about 12milligram/kg/hr) and for producing a sedative effect (for example, about0.3 to about 4.5 milligram/kg/hr) may be derived from the verysubstantial literature on 2,6-diisopropylphenol. The actual dosages ofthe 2,6-diisopropylphenol prodrugs, on a weight basis, may in some casesbe higher than for 2,6-diisopropylphenol itself because (a) themolecular weights of the prodrugs are higher and (b) release of2,6-diisopropylphenol from the prodrugs occurs at a finite rate.Furthermore, the anesthetist and/or physician would modify the dose toachieve the desired effect in any particular patient, in accordance withnormal skill in the art.

In another aspect, the invention relates to pharmaceutical compositionscomprising at least one of the compounds of the invention, as well aspharmaceutically acceptable prodrugs and salts of such compounds, in apharmaceutically acceptable vehicle, for use as anti-emetics. Theiradministration is indicated in subjects at risk of vomiting or who feelnauseous. As an example, the compounds are usefully co-administered tosubjects who are receiving treatments that induce nausea, such asvarious chemotherapy agents and surgical procedures. Accordingly, thisinvention provides methods for inhibiting nausea and vomiting byadministering the compound to a subject in an amount effective toinhibit nausea and vomiting. In the prophylactic or therapeutictreatment of nausea or vomiting, the compounds preferably are deliveredorally in a pharmaceutical composition. Accordingly, solid or liquidcarriers are appropriate delivery vehicles. However, parenteral routesof administration, such as inhalation or injection, also are useful aswell as topical and transdermal administration. For use as ananti-emetic, the compounds are effectively administered in amounts ofabout 50 milligram to about 2 gram.

In another aspect, the invention relates to pharmaceutical compositionscomprising at least one of the compounds of the invention, as well aspharmaceutically acceptable prodrugs and salts of such compounds, in apharmaceutically acceptable vehicle, for use as anti-convulsives toprevent or relieve seizures including, such as for example, epilepticseizures. This invention provides methods for inhibiting convulsionscomprising administering to a subject an amount of the compoundeffective to inhibit convulsions. In the prophylactic or therapeutictreatment of seizures the compounds preferably are delivered orally orparenterally. For use as an anti-convulsive, the compounds areeffectively administered in amounts of about 50 milligram to about 2gram daily.

In another aspect, the invention relates to pharmaceutical compositionscomprising at least one of the compounds of the invention, as well aspharmaceutically acceptable prodrugs and salts of such compounds, in apharmaceutically acceptable vehicle, for use as anti-pruritics toprevent or relieve itching. This invention provides methods ofinhibiting itching comprising administering the compound to a subject inan amount effective to inhibit itching. The compounds can treat bothexternal and internal itching. The source of itching can be any diseaseor exposure to a pruritic agent, such as poison ivy. In the prophylacticor therapeutic treatment of itching, the compounds preferably aredelivered topically in a pharmaceutical composition. Various creams andointments are appropriate delivery vehicles. For use as ananti-pruritic, the compounds are effectively administered in amounts ofabout 50 milligram to about 2 gram daily or rubbed into the skin atabout 0.01 to about 5 milligram per cm². Sub-sedative dose for pruritusmay be achieved at between about one-quarter and about one-tenth theanesthetic dose.

Invention compounds having structure A include but are not limited to:

Before the present compounds, compositions and methods are disclosed anddescribed, it is to be understood that this invention is not limited tospecific synthetic methods, specific pharmaceutical carriers, or toparticular pharmaceutical formulations or administration regimens, assuch may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularaspects only and is not intended to be limiting.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a bicyclic aromatic compound” includes mixtures ofbicyclic aromatic compounds, reference to “a pharmaceutical carrier”includes mixtures of two or more such carriers, and the like.

Certain pharmaceutically acceptable salts of the invention are preparedby treating the novel compounds of the invention with an appropriateamount of pharmaceutically acceptable base. Representativepharmaceutically acceptable bases are ammonium hydroxide, sodiumhydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide,magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copperhydroxide, aluminum hydroxide, ferric hydroxide, isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine,arginine, histidine, and the like. The reaction is conducted in water,alone or in combination with an inert, water-miscible organic solvent,at a temperature of from about 0° C. to about 100° C., preferably atroom temperature. The molar ratio of compounds of structural formula Ato base used is chosen to provide the ratio desired for any particularsalts. For preparing, for example, the ammonium salts of the startingmaterial, compounds of formula A can be treated with approximately oneequivalent of the pharmaceutically acceptable base to yield a neutralsalt. When calcium salts are prepared, approximately one-half a molarequivalent of base is used to yield a neutral salt, while for aluminumsalts, approximately one-third a molar equivalent of base will be used.

2,6-diisopropylphenol and the prodrugs of this invention preferably aredelivered as pharmaceutical compositions. “Pharmaceutical composition”refers to a composition suitable for pharmaceutical use in a subject.The pharmaceutical compositions of this invention comprise apharmacologically effective amount of a compound of the invention and apharmaceutically acceptable carrier. “Pharmacologically effectiveamount” refers to that amount of the compound effective to produce theintended pharmacological result, such as for example, inhibit oxidation,induce anesthesia, inhibit vomiting, inhibit convulsions, inhibititching, or inhibit inflammation. “Pharmaceutically acceptable carrier”refers to any of the standard pharmaceutical carriers, buffers, andexcipients, such as a phosphate buffered saline solution, aqueoussolutions of dextrose, and emulsions, such as an oil/water or water/oilemulsion, and various types of wetting agents and/or adjuvants. Suitablepharmaceutical carriers and formulations are described in Remington'sPharmaceutical Sciences, 19th Ed. (Mack Publishing Co., Easton, 1995).Preferred pharmaceutical carriers depend upon the intended mode ofadministration of the active agent.

The compounds of the invention can be formulated for administration in avariety of ways. Typical routes of administration include both enteraland parenteral. These include, without limitation, subcutaneous,intramuscular, intravenous, intraperitoneal, intramedullary,intrapericardiac, intrabursal, oral, sublingual, ocular, nasal, topical,transdermal, transmucosal, or anal. The mode of administration can be,such as for example, via swallowing, inhalation, injection or topicalapplication to a surface (such as for example, eyes, mucus membrane,skin).

Particular formulations typically are appropriate for specific modes ofadministration. Various contemplated formulations include, for example,aqueous solutions, solid formulations, aerosol formulations andtransdermal formulations.

Examples of aqueous solutions include, for example, water, saline,phosphate buffered saline, Hank's solution, Ringer's solution,dextrose/saline, glucose solutions and the like. The compositions cancontain pharmaceutically acceptable auxiliary substances as required toapproximate physiological conditions or to improve stability, appearanceor ease of administration, such as buffering agents, tonicity adjustingagents, wetting agents, detergents and the like. Additives can alsoinclude additional active ingredients such as bactericidal agents, orstabilizers. For example, the solution can contain sodium acetate,sodium lactate, sodium chloride, potassium chloride, calcium chloride,sorbitan monolaurate or triethanolamine oleate. These compositions canbe sterilized by conventional, well-known sterilization techniques, orcan be sterile filtered. The resulting aqueous solutions can be packagedfor use as is, or lyophilized, the lyophilized preparation beingcombined with a sterile aqueous solution prior to administration.

Aqueous solutions are appropriate for injection and, in particular, forintravenous injection. Intravenous injection is a particularlyappropriate means of delivery for using the compound as a hypnoticagent. The intravenous solution can include detergents and emulsifierssuch as lipids. Aqueous solutions also are useful for enteraladministration as tonics and administration to mucous or other membranesas, such as for example, nose or eye drops. The composition can containthe compound in an amount of about 1 milligram per milliliter to 100milligram per milliliter, more preferably about 10 milligram permilliliter.

Solid compositions are appropriate for enteral administration. They canbe formulated in the form of, such as for example, pills, tablets,powders or capsules. For solid compositions, conventional nontoxic solidcarriers can be used which include, for example, pharmaceutical gradesof mannitol, lactose, starch, magnesium stearate, sodium saccharin,talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.For oral administration, a pharmaceutically acceptable nontoxiccomposition is formed by incorporating any of the normally employedexcipients, such as those carriers previously listed, and generally10%-95% of active ingredient.

The carrier can be selected from various oils including those ofpetroleum, animal, vegetable or synthetic origin, for example, peanutoil, soybean oil, mineral oil, sesame oil, and the like. Suitablepharmaceutical excipients include starch, cellulose, talc, glucose,lactose, sucrose, gelatin, maltose, rice, flour, chalk, silica gel,magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk, glycerol, propylene glycol, water, ethanol,and the like.

A unit dosage form, such as a tablet, can have about 10 milligram toabout 2 gram of the compound.

Solid compositions are particularly useful for using the compound as ananti-emetic.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, bile salts and fusidic acidderivatives. In addition, detergents can be used to facilitatepermeation. Transmucosal administration can be through nasal sprays, forexample, or using suppositories.

For topical administration, the agents are formulated into ointments,creams, salves, powders and gels. In one aspect, the transdermaldelivery agent can be DMSO.

Transdermal delivery systems can include, such as for example, patches.

Topical administration is particularly useful for use of the compound asan anti-pruritic or in the treatment of wounds with an inflammatorycomponent such as burns, rashes and sunburns. However, sustainedadministration can deliver the compound for use as an anti-oxidant andanti-inflammatory agent internally.

For inhalation, the compound is preferably administered in the form ofan aerosol, liquid or solid. For aerosol administration, the compoundpreferably is supplied in finely divided form along with a surfactantand propellant. A surfactant may be required if the agent is immisciblein the propellant.

The surfactant preferably is soluble in the propellant. Representativeof such agents are the esters or partial esters of fatty acidscontaining from 6 to 22 carbon atoms, such as caproic, octanoic, lauric,palmitic, stearic, linoleic, linolenic, olesteric and oleic acids withan aliphatic polyhydric alcohol or its cyclic anhydride such as, forexample, ethylene glycol, glycerol, erythritol, arabitol, mannitol,sorbitol, the hexitol anhydrides derived from sorbitol, and thepolyoxyethylene and polyoxypropylene derivatives of these esters. Mixedesters, such as mixed or natural glycerides, can be employed. Thesurfactant can constitute 0.1%-20% by weight of the composition,preferably 0.25%-5%.

The balance of the composition is ordinarily propellant. Liquefiedpropellants are typically gases at ambient conditions, and are condensedunder pressure. Among suitable liquefied propellants are the loweralkanes containing up to 5 carbons, such as butane and propane; andpreferably fluorinated or fluorochlorinated alkanes. Mixtures of theabove can also be employed. In producing the aerosol, a containerequipped with a suitable valve is filled with the appropriatepropellant, containing the agent as a solution or as finely dividedparticles and surfactant. The ingredients are thus maintained at anelevated pressure until released by action of the valve.

A nebulizer or aerosolizer device for administering compounds typicallydelivers a dose of about concentration of between about 1 and 50milligram per inhalation.

Delivery by inhalation is particularly effective for delivery torespiratory tissues for the treatment of respiratory conditionsincluding an inflammatory component. Delivery of large doses byrespiration also can induce sedation or anaesthesia. Anesthesia may beachieved by means of continuous inhalation such as occurs with2,6-diisopropylphenol, ether, or other conventional anesthetics.Induction may occur at doses between about 200 milligram and about 400milligram inhaled over a period of a few minutes (such as for example,about 5 to about 15 minutes). Sedation may be maintained thereafter at adose of about 200 milligram to about 400 milligram per hour for as longas is needed.

In preparing pharmaceutical compositions of the present invention, itcan be desirable to modify the complexes of the present invention toalter their pharmacokinetics and biodistribution. For a generaldiscussion of pharmacokinetics, See, Remington's Phamaceutical Sciences,supra, Chapters 37-39. A number of methods for altering pharmacokineticsand biodistribution are known to one of ordinary skill in the art.Examples of such methods include protection of the complexes in vesiclescomposed of substances such as proteins, lipids (for example,liposomes), carbohydrates, or synthetic polymers.

Single or multiple administrations of the compositions can be carriedout with dose levels and pattern being selected by the treatingphysician. In any event, the pharmaceutical formulations should providea quantity of a compound sufficient to treat the patient effectively.

The total effective amount of a compound of the present invention can beadministered to a subject as a single dose, either as a bolus or byinfusion over a relatively short period of time, or can be administeredusing a fractionated treatment protocol, in which the multiple doses areadministered over a more prolonged period of time. One skilled in theart would know that the concentration of a compound of the presentinvention required to obtain an effective dose in a subject depends onmany factors including the age and general health of the subject, theroute of administration, the number of treatments to be administered andthe judgrament of the prescribing physician. In view of these factors,the skilled artisan would adjust the dose so as to provide an effectivedose for a particular use.

EXAMPLES

Used herein, the following abbreviations have the following meanings: Merefers to methyl (CH₃—), Et refers to ethyl (CH₃CH₂—), i-Pr refers toisopropyl ((CH₃)₂CH₂—), t-Bu or tert-butyl refers to tertiary butyl((CH₃)₃CH—), Ph refers to phenyl, Bn refers to benzyl (PhCH₂—), Bzrefers to benzoyl (PhCO—), MOM refers to methoxymethyl, Ac refers toacetyl, TMS refers to trimethylsilyl, TBS refers toter-butyldimethylsilyl, Ms refers to methanesulfonyl (CH₃SO₂—), Tsrefers to p-toluenesulfonyl (p-CH₃PhSO₂—), Tf refers totrifluoromethanesulfonyl (CF₃SO₂—), TfO refers totrifluoromethanesulfonate (CF₃SO₃—), DMF refers toN,N-dimethylformamide, DCM refers to dichloromethane (CH₂Cl₂), THFrefers to tetrahydrofuran, EtOAc refers to ethyl acetate, Et₂O refers todiethyl ether, MeCN refers to acetonitrile (CH₃CN), NMP refers to1-N-methyl-2-pyrrolidinone, DMA refers to N,N-dimethylacetamide, DMSOrefers to dimethylsulfoxide, DCC refers to1,3-dicyclohexyldicarbodiimide, EDCI refers to1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, Boc refers totert-butylcarbonyl, Fmoc refers to 9-fluorenylmethoxycarbonyl, TBAFrefers to tetrabutylammonium fluoride, TBAI refers to tetrabutylammoniumiodide, TMEDA refers to N,N,N,N-tetramethylethylene diamine, Dess-Martinperiodinane or Dess Martin reagent refers to1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, DMAP refers to4-N,N-dimethylaminopyridine, (i-Pr)₂NEt or DIEA or Hunig's base refersto N,N-diethylisopropylamine, DBU refers to1,8-Diazabicyclo[5.4.0]undec-7-ene, (DHQ)₂AQN refers to dihydroquinineanthraquinone-1,4-diyl diether, (DHQ)₂PHAL refers to dihydroquininephthalazine-1,4-diyl diether, (DHQ)₂PYR refers to dihydroquinine2,5-diphenyl-4,6-pyrimidinediyl diether, (DHQD)₂AQN refers todihydroquinidine anthraquinone-1,4-diyl diether, (DHQD)₂PHAL refers todihydroquinidine phthalazine-1,4-diyl diether, (DHQD)₂PYR refers todihydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether, LDA refers tolithium diisopropylamide, LiTMP refers to lithium2,2,6,6-tetramethylpiperidinamide, n-BuLi refers to n-butyllithium,t-BuLi refers to tert-butyl lithium, IBA refers to1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide, OsO₄ refers to osmiumtetroxide, m-CPBA refers to meta-chloroperbenzoic acid, DMD refers todimethyl dioxirane, PDC refers to pyridinium dichromate, NMO refers toN-methyl morpholine-N-oxide, NaHMDS refers to sodiumhexamethyldisilazide, LiHMDS refers to lithium hexamethyldisilazide,HMPA refers to hexamethylphosphoramide, TMSCl refers to trimethylsilylchloride, TMSCN refers to trimethylsilyl cyanide, TBSCI refers totert-butyldimethylsilyl chloride, TFA refers to trifluoroacetic acid,TFAA refers to trifluoroacetic anhydride, AcOH refers to acetic acid,Ac₂O refers to acetic anhydride, AcCl refers to acetyl chloride, TsOHrefers to p-toluenesulfonic acid, TsCl refers to p-toluenesulfonylchloride, MBHA refers to 4-methylbenzhydrylamine, BHA refers tobenzhydrylamine, ZnCl₂ refers to zinc (II) dichloride, BF₃ refers toboron trifluoride, Y (OTf)₂ refers to yttrium (III)trifluoromethanesulfonate, Cu(BF₄)₂ refers to copper (II)tetrafluoroborate, LAH refers to lithium aluminum hydride (LiAlH₄),NaHCO₃ refers to sodium bicarbonate, K₂CO₃ refers to potassiumcarbonate, NaOH refers to sodium hydroxide, KOH refers to potassiumhydroxide, LiOH refers to lithium hydroxide, HCl refers to hydrochloricacid, H₂SO₄ refers to sulfuric acid, MgSO₄ refers to magnesium sulfate,and Na₂SO₄ refers to sodium sulfate. 1H NMR refers to proton nuclearmagnetic resonance, 13C NMR refers to carbon 13 nuclear magneticresonance, NOE refers to nuclear overhauser effect, NOESY refers tonuclear overhauser and exchange spectroscopy, COSY refers to homonuclearcorrelation spectroscopy, HMQC refers to proton detected heteronuclearmultiplet-quantum coherence, HMBC refers to heteronuclear multiple-bondconnectivity, s refers to singlet, br s refers to broad singlet, drefers to doublet, br d refers to broad doublet, t refers to triplet, qrefers to quartet, dd refers to double doublet, m refers to multiplet,ppm refers to parts per million, IR refers to infrared spectrometry, MSrefers to mass spectrometry, HRMS refers to high resolution massspectrometry, EI refers to electron impact, FAB refers to fast atombombardment, CI refers to chemical ionization, HPLC refers to highpressure liquid chromatography, TLC refer to thin layer chromatography,R_(f) refers to, R_(f) refers to retention time, GC refers to gaschromatography, min is minutes, h is hours, rt or RT is roomtemperature, gram is grams, mg is milligrams, L is liters, mL ismilliliters, mol is moles and mmol is millimoles.

For all of the following examples, standard work-up and purificationmethods can be utilized and will be obvious to those skilled in the art.Synthetic methodologies that make up the invention are shown in Schemes1-3. These Schemes are intended to describe the applicable chemistrythrough the use of specific examples and are not indicative of the scopeof the invention.

Example 1 Propofol Hemisuccinate

To a solution of 2,6-diisopropylphenol (4.0 g, 22.4 mmol) in 15 mL ofEt₃N was added succinic anhydride (2.8 g, 28 mmol) and a catalyticamount of DMAP (10 mg) under N₂ atmosphere. The reaction mixture wasstirred at ambient temperature overnight. The solvent was removed undervacuum and the residue was dissolved in water (30 mL) and added to acold solution of 1N HCl (150 mL). The precipitate was filtered anddried. Recrystallization from ethanol-water (2:1) mixture gave2,6-diisopropylphenyl hemisuccinate as a white crystalline solid. Yield:5.8 gram (94%).

¹H-NMR (CDCl₃) δ ppm: 1.2 (d, 12H), 2.82-2.84 (m, 2H), 2.85-3.0 (m, 4H),7.1-7.21 (m, 3H).

Example 2 N-(2-pyrrolidin-1-yl-ethyl)-succinamic acid2,6-diisopropylphenyl ester

To a solution of propofol hemisuccinate (2.0 g, 7.2 mmol) in THF-CH₂Cl₂(1:1, 60 mL) was added EDCI (1.72 g, 9 mmol) followed by HOBt (1.37 g, 9mmol). The reaction mixture was stirred at ambient temperature for 15min and 1-(2-aminoethyl)pyrrolidine (0.912 g, 8 mmol) was added andstirring was maintained overnight. 10% aqueous citric acid (50 ml) wasadded and the mixture was extracted with CH₂Cl₂ (100 ml×2). The organiclayer was washed with brine and dried over anhydrous MgSO₄. The solventwas removed and the product was purified by silica gel columnchromatography using acetone with 1% Et₃N. Removal of the solvent gavethe product as an oil. Yield: 2.47 gram (92%)

¹H-NMR (CDCl₃) δ ppm: 1.2 (d, 12H), 1.8 (m, 4H), 2.2 (d, 1H), 2.6 (m,8H), 2.95 (m, 4H), 3.36 (m, 2H), 7.2 (m, 3H).

Example 3 N-(2-piperidin-1-yl-ethyl)-succinamic acid2,6-diisopropylphenyl ester

Prepared according to example 2. Yield: 86%

¹H-NMR (CDCl₃) δ ppm: 1.2 (d, 12H), 1.44 (m, 2H), 1.6 (m, 4H), 2.42 (t,5H), 2.6 (t, 2H), 2.90 (m, 4H), 3.32 (m, 4H), 7.18 (m, 3H).

Example 4 N-(2-dimethylaminoethyl)-succinamic acid2,6-diisopropyl-phenyl ester

Prepared according to example 2. Yield: 64%—Rf: 0.55 (in 50%MeOH—CH₂Cl₂) ¹H NMR (300 MHz, CD₃OD) δ ppm: 1.2 (d, 12H), 2.3 (s, 6H),2.45 (t, 2H), 2.6 (t, 2H), 3.0 (m, 3H), 3.36 (m, 3H), 7.2 (m, 3H)

Example 5 N-(2-diethylaminoethyl)-succinamic acid 2,6-diisopropylphenylester

Prepared according to example 2. Yield: 50%; Rf: 0.6 (in 20%MeOH—CH₂Cl₂)

¹H NMR (300 MHz, CDCl₃) δ ppm: 1 (t, 6H), 1.2 (d, 12H), 2.57 (m, 6H),2.62 (t, 2H), 2.9 (m, 2H), 3.2 (t, 2H), 3.3 (m, 2H), 6.2 (br s, 1H), 7.2(s, 3H)

Example 6 N-(2-Diisopropylaminoethyl)-succinamic acid2,6-diisopropyl-phenyl ester

Prepared according to example 2. Yield: 99%; Rf: 0.5 (in 20%MeOH—CH₂Cl₂+1% Et₃N)

¹H NMR (300 MHz, CDCl₃) δ ppm: 1.0 (d, 12H), 1.2 (d, 12H), 2.6 (m, 4H),2.9 (m, 2H), 3.1 (m, 4H), 3.35 (m br, 2H) 7.2 (s, 3H)

Example 7 N-(2-morpholin-4-yl-ethyl)-succinamic acid2,6-diisopropylphenyl ester

Prepared according to example 2. Yield: 68%; Rf: 0.8 (20% MeOH—CH₂Cl₂+1%Et₃N))

¹H NMR (300 MHz, CDCl₃) δ ppm: 1.2 (d, 12H), 2.45 (m, 6H), 2.6 (t, 2H),2.9 (m, 2H), 3.12 (t, 2H), 3.35 (m, 2H), 3.7 (m, 4H), 6.15 (t br, 1H),7.2 (m, 3H)

Example 8 N-(2-pyrrolidin-1-yl-ethyl)-succinamic acid2,6-diisopropylphenyl ester hydrochloride

A solution of N-(2-Pyrrolidin-1-yl-ethyl)-succinamic acid2,6-diisopropylphenyl ester (700 mg) in 100 ml of ether was cooled to 0°C. and dry HCl gas was bubbled in for 10 min. The precipitate wasfiltered, washed with ether and dried under high vacuum to yieldN-(2-Pyrrolidin-1-yl-ethyl)-succinamic acid 2,6-diisopropylphenyl esterhydrochloride as a white crystalline solid. Yield: 590 mg (77%).

¹H-NMR (D₂O) δ ppm: 1.05 (d, 12H), 1.85 (m, 2H), 2.05 (m, 2H), 2.6 (m,2H), 2.8 (m, 2H), 2.95 (m, 4H), 3.2 (m, 2H), 3.45 (m, 2H), 3.55 (m, 2H),7.2 (m, 3H).

Example 9 N-(2-piperidin-1-yl-ethyl)-succinamic acid2,6-diisopropylphenyl ester hydrochloride

Yield: 584 mg (86%).

¹H-NMR (D₂O) δ ppm: 1.05 (d, 12H), 1.3 (m, 1H), 1.6 (m, 3H), 1.8 (m,2H), 2H), 2.8 (m, 4H), 2.95 (m, 2H), 3.1 (m, 2H), 3.4 (m, 2H), 3.5 (m,2H), 7.2 (m, 3H).

Example 10 N-(2-dimethylamino-ethyl)-succinamic acid2,6-diisopropyl-phenyl Ester Hydrochloride

Prepared according to example 8. Yield: 49%

¹H-NMR (D₂O) δ ppm: 0.98 (d, 12H), 2.57 (t, 2H), 2.75 (m, 8H), 2.9 (t,2H), 3.1 (t, 2H), 3.45 (t, 2H), 7.15 (m, 3H)

Example 11 2-diethylamino-ethyl)-succinamic acid 2,6-diisopropyl-phenylester hydrochloride

Prepared according to example 8. Yield: 49%

¹H-NMR (D₂O) δ ppm: 0.98 (d, 12H), 1.11 (t, 6H), 2.57 (t, 2H), 2.75 (m,2H), 2.9 (t, 2H), 3.1 (m, 6H), 3.45 (t, 2H), 7.15 (m, 3H), 7.45 (s, 1H).

Example 12 N-(2-diisopropylamino-ethyl)-succinamic acid2,6-diisopropyl-phenyl ester hydrochloride

Prepared according to example 8. Yield: 99%

¹H-NMR (D₂O) δ ppm: 0.98 (d, 12H), 1.17 (d, 12H), 2.59 (t, 2H), 2.75 (m,2H), 2.9 (t, 2H), 3.1 (t, 2H), 3.38 (t, 2H), 3.6 (m, 2H), 7.15 (m, 3H),7.45 (s, 1H).

Example 13 N-(2-morpholin-4-yl-ethyl)-succinamic acid2,6-diisopropylphenyl ester hydrochloride

Prepared according to example 8. Yield: 69%

¹H-NMR (D₂O) δ ppm: 0.98 (d, 12H), 2.59 (t, 2H), 2.75 (m, 2H), 2.9 (t,2H), 3.04 (m br, 2H), 3.17 (t, 2H), 3.38 (m br, 2H), 3.48 (t, 2H), 3.61(m br, 2H), 3.89 (m br, 2H), 7.15 (m, 3H).

Example 14 N-(2-dibutylaminoethyl)-succinamic acid2,6-diisopropyl-phenyl ester

Prepared according to example 2. Yield: 94%; Rf: 0.55 (in 5% MeOH-DCM)

¹H NMR (300 MHz, CDCl₃) δ ppm: 0.95 (t, 6H), 1.2 (d, 12H), 1.22-1.42 (m,8H), 2.4 (t, 4H), 2.45-2.6 (m, 4H), 2.9 (m, 2H), 3.02 (t, 2H), 3.3 (m,2H), 7.1 (m, 3H)

Example 15 N-(2-dibutylaminoethyl)-succinamic acid2,6-diisopropyl-phenyl ester hydrochloride

Prepared according to example 8. Yield: 92%.

¹H NMR (300 MHz, D₂O) δ ppm: 0.77 (t, 6H), 0.99 (d, 12H), 1.18 (m, 4H),1.48 (m, 4H) 2.58 (m, 2H), 2.75 (m, 2H), 2.9 (m, 2H), 3.0 (m, 4H), 3.12(m, 2H), 3.42 (m, 2H), 7.1 (m, 3H)

Example 16 In-vitro hydrolysis of N-(2-piperidin-1-yl-ethyl)-succinamicacid 2,6-diisopropylphenyl ester hydrochloride

A solution was prepared by dissolving 5 mg ofN-(2-Piperidin-1-yl-ethyl)-succinamic acid 2,6-diisopropylphenyl esterhydrochloride in 12 mL of pH=7.4 phosphate buffer. The solution wasincubated at 37° C. and aliquots were drawn at 5, 15, 30 and 45 minutesand analyzed by reverse phase HPLC. A plot of UV absorption versus timeclearly demonstrates the hydrolysis of the prodrug at pH=7.4.

Example 17 Ph stability of N-(2-piperidin-1-yl-ethyl)-succinamic acid2,6-diisopropylphenyl ester hydrochloride

A solution was prepared by dissolving 100 mg ofN-(2-Piperidin-1-yl-ethyl)-succinamic acid 2,6-diisopropylphenyl esterhydrochloride in 10 mL of pH=4.1 sodium acetate buffer. The buffer wasprepared by adding NaOH to a 20% aqueous acetic acid solution until thedesired pH was reached. The solution was incubated at ambienttemperature and analyzed by LC-MS after 48 hours. No trace ofdecomposition was observed.

Example 18 In-Vivo Induction of Anesthesia

Prodrugs were formulated as aqueous isotonic solutions at pH 7.4 insterile water before administration to animals. Female mice wereobtained from Charles River Laboratories (Wilmington, Mass.). The volumeof injection was set at 110 mL/kg/animal and animals were dosed IP at100 mg/kg, 125 mg/kg, 150 mg/kg and 200 mg/kg. The monitoring ofdistinguishable levels of sedation started immediately after aninjection and was continued for a 2-h period post-injection. Thesedation level was graded according to the behavioral and reflexactivity of animals injected with progressively increasing doses of eachcompound. Animals were graded as alert and normal when there was noobservable change in their behavior; alert with decreased motor activitywhen ataxia with some ability to walk was observed; and awake andrecumbent when loss of righting reflex occurred. Animals reachingsomnolence but retaining response to painful stimuli (toe or tail pinch)were graded as sedated with normal reflexes, whereas animals that lostresponse to painful stimuli were graded as sedated with decreasedreflexes (anesthetic level of sedation). Death resulting from theoverdose was also recorded as a last level.

N-(2-Pyrrolidin-1-yl-ethyl)-succinamic acid 2,6-diisopropylphenyl esterhydrochloride

150 mg/kg: Onset of sedation −2 minutes post injection; Fullanesthesia—4 minutes post injection; Duration of anesthesia—10 minutes(14 minutes post injection).

200 mg/kg: Onset of sedation −2 minutes post injection; Fullanesthesia—4 minutes post injection; Duration of anesthesia—21 minutes(25 minutes post injection).

N-(2-Piperidin-1-yl-ethyl)-succinamic acid 2,6-diisopropylphenyl esterhydrochloride

100 mg/kg: Onset of sedation −2 minutes post injection; Fullanesthesia—not reached; Duration of anesthesia—11 minutes (13 minutespost injection).

125 mg/kg: Onset of sedation −2 minutes post injection; Fullanesthesia—not reached; Duration of sedation—13 minutes (15 minutes postinjection).

200 mg/kg: Onset of sedation −2 minutes post injection; Fullanesthesia—5 minutes post injection; Duration of anesthesia—12 minutes(16 minutes post injection).

The present invention provides pH sensitive, water soluble derivativesof 2,6-diisopropylphenol and methods of using these compounds. Whilespecific examples have been provided, the above description isillustrative and not restrictive. Many variations of the invention willbecome apparent to those skilled in the art upon review of thisspecification. The scope of the invention should, therefore, bedetermined not with reference to the above description, but insteadshould be determined with reference to the appended claims along withtheir full scope of equivalents.

1. A compound of formula A:

wherein: R₁ is hydrogen, alkyl, or aryl; Each X is independently C₁₋₁₀alkyl; Y is heteroaryl, saturated heterocyclic, or NR₂R₃, R₂ and R₃ areindependently hydrogen, alkyl, or R₂ and R₃, together with the nitrogenatom to which they are attached, combine to form a saturatedheterocyclic or heteroaryl ring; or pharmaceutically acceptable salts ofany of the foregoing.
 2. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a pharmacologically effectiveamount of a compound according to claim
 1. 3. A pharmaceuticalcomposition of claim 2, wherein the pharmaceutically acceptable carrieris selected from an aqueous solution, an injectable solution, anaeorsolizer, an inhaler or a transdermal delivery vehicle.
 4. Apharmaceutical composition of claim 2 contained in a unit dosage form.5. The pharmaceutical composition of claim 2 wherein thepharmaceutically acceptable carrier comprises a transdermal deliveryvehicle, wherein the pharmaceutically acceptable carrier contains adetergent, an emulsifier or liposomes.
 6. The pharmaceutical compositionof claim 2 in the form of an injectable solution wherein theconcentration of the compound in the injectable solution is betweenabout 0.5 milligram per milliliter to about 200 milligram permilliliter.
 7. The pharmaceutical composition of claim 2 contained in aunit dosage form wherein the unit dosage form contains about 0.5milligram to about 1.2 gram of the compound.
 8. A method for inhibitingoxidation of biological material comprising contacting the material withan effective amount of a compound of claim
 1. 9. A method for thetreatment of a condition having an inflammatory component, the methodcomprising administering to a subject in need thereof an effectiveamount of at least one compound according to claim
 1. 10. The method ofclaim 9, wherein the condition is selected from arthritis, a pathologiccondition of the nervous system, a neurodegenerative disease, trauma tothe central nervous system, Friedrich's disease, Parkinson's disease,Alzheimer's disease, Huntington's disease, Pick disease, amyotrophiclateral sclerosis, multiple sclerosis, or a spinal cord injury.
 11. Amethod for the treatment of a respiratory condition, the methodcomprising administering to a subject in need thereof an effectiveamount of at least one compound according to claim
 1. 12. The method ofclaim 11, wherein the respiratory condition is selected from acidaspiration, adult/infant respiratory distress syndrome, airwayobstructive disease, asthma, bronchiolitis, bronchopulmonary dysplasia,cancer, chronic obstructive pulmonary disease, cystic fibrosis,emphysema, HIV-associated lung disease, idiopathic pulmonary fibrosis,immune-complex-mediated lung injury, exposure to an oxidizing agent,ischemia-reperfusion injury, mineral dust pneumoconiosis, drug-inducedlung disease, silo-filler's disease, exposure to dust, exposure toozone, exposure to hyperoxia, exposure to air pollution, exposure todiesel exhaust, exposure to nitric oxide, exposure to nitrogen dioxide,exposure to sulfur dioxide, exposure to tobacco smoke, or exposure toother combustion byproducts.
 13. The method of claim 11 wherein thecompound is administered by inhalation as an aerosol, mist or powder.14. A method for inducing anesthesia, the method comprisingadministering to a subject in need thereof an effective amount of atleast one compound according to claim 1, wherein the compound accordingto claim 1 is administered in the form of an intravenous injection of anaqueous composition comprising the compound.
 15. The method of claim 11wherein the compound is administered by inhalation.
 16. A method forinhibiting nausea and vomiting, the method comprising administering to asubject in need thereof an effective amount of at least one compoundaccording to claim
 1. 17. A method for the treatment of epileptic orconvulsive disorders, the method comprising administering to a subjectin need thereof an effective amount of at least one compound accordingto claim
 1. 18. A method for the treatment of pruritus, the methodcomprising administering to a subject in need thereof an effectiveamount of at least one compound according to claim
 1. 19. A method forthe treatment of a cancer, the method comprising administering to asubject in need thereof an effective amount of at least one compoundaccording to claim
 1. 20. A method for treating cancer, the methodcomprising administering to a subject in need thereof an effectiveamount of at least one compound according to claim 1 in combination withat least one other chemotherapeutic agents selected from Busulfan,Carboplatin, Cisplatin, Cyclophosphamide, Cytosine arabinoside,Etoposide, 5-Fluorouracil, Gemzar, Melphalan, Methotrexate,Mitoxantrone, Taxol, Interferon, Fareston, Arzoxifene, Evista, orTamoxifen.
 21. The method of claim 20 wherein the cancer is selectedfrom mammary cancer, prostate cancer, kidney cancer, Karposi's sarcoma,colon cancer, cervical cancer, lung cancer, cutaneous T-cell lymphoma,cancer of the head and neck, cancers of the aerodigestive pathway, skincancer, bladder cancer, sarcomas, leukoplakias, or acute promyelocyticleukemia.
 22. The method of claim 21 wherein the cancer is selected frommammary cancer, prostate cancer, kidney cancer, Karposi's sarcoma, coloncancer, cervical cancer, lung cancer, cutaneous T-cell lymphoma, cancerof the head and neck, cancers of the aerodigestive pathway, skin cancer,bladder cancer, sarcomas, leukoplakias, or acute promyelocytic leukemia.23. A compounds selected from:

and pharmaceutically acceptable salts of any of the foregoing.